Besides his son George, William had a daughter named Frances "Fanny" Martha who married Jonathan Burrall on May 20, 1793 in Goshen. During the American Revolution, Jonathan had served as assistant paymaster for the American army, and afterwards was assistant postmaster-general, cashier of the United States branch bank of New York, and manager of the New York state lotteries. The couple had three daughters, including Emily (George's niece) who married Ogden Hoffman, a much celebrated lawyer from a prominent family who represented Orange County in the Assembly and held several other important political posts, including several terms in Congress; Emily's sister, Frances Amelia Burrall, married Ogden Hoffman's first cousin Murray Hoffman, a New York jurist. (Other members of this distinguished Hoffman clan include Colonel Wickham Hoffman, United States Minister to Denmark; and Matilda Hoffman, who was engaged to Washington Irving.) George and his family were one of several Wickham families living in Orange County at the time, including his father's first cousin William and second cousin Noyes Wickham. As documented by his descendant Evelyn Wornham Wickham, Noyes moved to Orange County in about 1783 from Suffolk County on Long Island, while William left the area in 1790 to become the first permanent white settler of Schuyler County, NY.

George began his business ventures with his father and developed a life-long enthusiasm for the transportation industry. In 1798, the Wickhams had an ownership interest in the stagecoach line of Anthony Dobbin, who had an exclusive right to operate one from New York City to Goshen. The first turnpike in Orange County, the Orange Turnpike, was chartered in 1800, and both George and his father were shareholders, with George also serving as a Commissioner for receiving subscriptions. George was elected President of the Goshen and Wallkill Turnpike Company on September 19, 1809, but following a lawsuit in 1819, the company was dissolved because it could not make its payments. George was also active in chartering the Minisink and Goshen Turnpike Company, the Mount Hope and Lumberland Turnpike Road, and Merritt's Island Turnpike. In addition, he had ownership interests in the Great Island Turnpike and the Newburgh and Cochecton Turnpike. In 1825, he was elected a director of the Delaware and Hudson Canal Company, which was established to bring coal from northeastern Pennsylvania to the markets of New York. Although the canal was later abandoned, the company continued to prosper as a railway. In 1832, he was one of 66 men to petition the legislature to charter a railroad to serve southern New York. This request was granted with the charter of the New York and Erie Railroad Company, and George was elected one of the directors. According to local tradition, the railroad ran through Goshen because of George's influence. On September 23, 1841, the New York and Erie Railroad Company began service to Goshen, cutting the transit time to New York City from two days to four hours. The festive occasion was marked by music, cannon fire, and a speech by George to a crowd that included Governor William H. Seward.

George's greatest personal business success by far was the Bank of Orange County, established to fill the void created by the demise of the first Bank of the United States in 1811. The bank charter was granted by a legislative bill on April 6, 1813, which was shepherded through the State Senate by George's political ally James W. Wilkin. With the support of Nathaniel Prime, the second richest man in New York City, George formed and became President and Director of the bank on June 7, 1813, positions that he held for over 30 years until his death (see picture of banknote). George also maintained extensive agriculture and lumbering interests, frequently trading in such items as butter, tea, veal, and lumber. To conduct his lumbering operations, George purchased a considerable amount of land in the Town of Lumberland and had mills at Ten Mile River and Forestburgh. During the 1820s, he was involved in a resort project to develop Chechunk Springs, which were believed to be of medicinal value, but the project collapsed after the springs stopped flowing when the Wallkill River was re-routed. In addition, he built a hotel in 1841, commonly known as Wickham's Hotel, across the street from the train station in Goshen. The structure, formally known as the Pavilion, was a popular gathering spot and stood until 1983, when it was destroyed by a severe fire. By the time of the death of his wealthier father from gout in 1814, tax assessment records indicate that George had already become the richest man in Goshen. While George never held elected public office, he was known to be close with many of the area's leading politicians. In the election of 1833, George was a supporter of Isaac R. Van Duzer, a candidate for the Assembly. The Independent Republican, a Goshen newspaper, commented: "Who does not know that I.R. Van Duzer is the attorney and a Director of the Orange County Bank? Who does not know that he owes his political existence to the President of that institution, under whose guidance and direction he acts?" Van Duzer went on to victory in the election.

George was also involved in many civic and community activities. From 1807 through 1839, he served as a Commissioner for a public project to drain the so-called "Drowned Lands," a massive swamp that extended from Sussex County, New Jersey to a few miles south of the village of Goshen. Using state funds, he completed in 1835 a canal through his property that successfully drained the swamp after previous attempts failed. The "Drowned Lands" soon became known as the "Black Dirt Region," an extremely fertile area characterized by deep, peaty soils. A colorful conflict called the Muskrat and Beaver Wars erupted when millers from New Hampton tried to dam the canal, provoking farmers to destroy the dams several times. As required under New York State law at the time, George also joined the state militia, becoming a Captain in the cavalry by 1796. He was a Major by 1798, a Commander by 1803, and a Lieutenant-Colonel by 1810. After 20 years of military service, George was appointed to the rank of Brigadier General in 1814, with command of the cavalry units for the Counties of Orange, Rockland, Ulster, Dutchess, and Putnam. Although the War of 1812 was raging by then, George had very little wartime experience, unlike his second cousin Williams Carter Wickham who held the same military rank several decades later in Virginia. George's limited involvement in the war included dispatching troops to defend New York City after the British burned Washington. Highly concerned that New York might be burned next, the state hastily ordered George to "organize and send to New York immediately two full troops of cavalry of his brigade with one major to be selected by him." George also sat on a committee for repairing the fortifications at West Point. During the rest of the war, he spent a good part of his time securing the charter for his bank and organizing it. George was also active in an Orange County farm organization called the Agricultural Society, which was formed on May 28, 1818, with George being 2nd Vice President. In 1815, he was a Trustee of Farmers Hall Academy and in 1822 he participated in the effort to bring back the remains of Goshen militiamen killed in the Battle of Minisink of 1779.

At age 50, George married Bridget McDonell on August 8, 1822 at St. James Episcopal Church. Bridget and her brother John had been foster children raised by George's father after their own father, an Irish immigrant, died of cholera. George and Bridget had no descendants, but frequently looked after the two surviving children of George's niece Emily Hoffman after her death. The two boys, Charles and Ogden, spent many a day in Goshen watching the local trotter-horse races while their father was away on business for extended periods of time. After studying law at Harvard, Ogden moved to San Francisco in 1850 and in 1851 he became the first federal judge for the United States District Court for the Northern District of California. He held the post for an incredible 40 years, becoming one of the most influential judges in California history. He set many important precedents in land and admiralty law, but is best remembered for his refusal to discriminate against Asian-Americans, despite pressure from the public and even other judges to do so.

George died on November 16, 1845, followed by his wife's death on February 5, 1864. At the time of his death, George owned a mansion, three farms, a hotel, 1,372 shares in the Bank of Orange County, and numerous other land holdings, securities, and notes. Although he certainly died a wealthy man, George could have achieved even greater success if his turnpike investments had been more fruitful. Local regulations capped the tolls turnpikes could charge, preventing many of them from earning reasonable returns. On November 17th, the Orange County Board of Supervisors passed a motion that it was "resolved that the Board attend in a body the funeral of General George D. Wickham tomorrow at 2 o'clock," with the minutes further indicating that the Board did attend. A large memorial to George and his wife Bridget was placed on the inside back wall of St. James Episcopal Church, which both George and his father generously supported. Noting that for many years George was a warden of the church, the memorial consists of a polished marble plaque that is about two and one-half feet square, which is surrounded by a church-like structure about six feet high including a pair of marble pillars (see picture). In 1994, the Goshen Chamber of Commerce published a well researched, 70-page book titled George Duncan Wickham: A Biography by Henry Pomares in which a more complete account of George's career and legacy can be found.