William received a law degree from Yale and was admitted to the bar in 1841 after getting practical training in the office of Hon. Selah B. Strong of Setauket, NY. He began to practice law in nearby Patchogue until he moved for good to Cutchogue in 1854. In 1847, 1850, 1853, and 1875 he was elected District Attorney of Suffolk County, gaining a reputation as a faithful public steward. He was elected to the New York State Constitutional Convention in 1866. In 1873 and 1879, he was nominated for County Judge and Surrogate, but was defeated due to the prevailing political climate. Throughout his career, William received many honors and built a conspicuously successful law practice, known as Wickham and Case, where he was the senior partner. Among his many clients was the Long Island Railroad and the Shinnecock Indian Reservation. Delegations of braves from the Reservation would stop by the house, until virtually all of the men perished while salvaging a ship off the South Shore. During the time of the Civil War, William was known for his abolitionist sympathies, despite being a Democrat and having a Virginia-based cousin, Williams Carter Wickham, who was a Confederate general. An interesting stand-off occured in 1861 at William's church, the Presbyterian Church in Cutchogue. The Civil War was just starting and some members of the congregation were incensed by the abolitionist sermons given by the pastor, Reverend Sinclair. A meeting was called, and William, the pastor, and many other members of the congregation were locked out of the church. As a result, they decided to build a new church across the street, Cutchogue's Congregational Church. After some sixty years, differences were finally forgotten and the old Congregational church building became what is today the Cutchogue Free Library.

One of William's brothers was the largest farmer in Suffolk County, and his brother James, who moved to Brooklyn in his twenties, owned and operated a successful grocery store there called Wickham and Corwin. By his early forties, James was quite wealthy and purchased at auction in 1850 the Albertson estate in Cutchogue, which included a mansion and eighty acres of farmland. James and his wife Frances hired a number of servants and field-workers to operate the farm, but after four years he got in an argument with one of his field hands, Nicholas Behan, about Behan's hustling one of the house servants, after his proposal for marriage to her was rejected. Behan was fired for this offense, but at about midnight several days later, he crept into the house with an ax and sneaked into the bedroom where James and Frances were sleeping. Servants in the house heard their screams of "Murder!" and "Spare our lives!", but fearing they were next, exited from a second story window and raced to spread the alarm. Would-be rescuers soon arrived to find the horribly gashed couple laying in vast pools of blood, with a bloody trail leaving the scene. Frances died almost immediately, while James lingered on for several more hours before dying of his severe wounds, which included many direct blows to the head and face (see murder weapon). A hat left at the scene confirmed that Behan was responsible for this grotesque crime and shortly thereafter he was found in a nearby swamp beneath thick brush and half-buried in the muck, his escape thwarted by the crime scene's location near the waterfront. Surrounded by an armed crowd of more than one thousand men, he was taken to the county jail in Riverhead, where a special prosecutor was named since James' brother William was the County District Attorney. A conviction soon ensued, and on December 15, 1854, Behan became the last person to be hanged in Suffolk County and his body was buried in an unmarked grave. Because James survived his wife by a few hours, his estate remained in the Wickham family, rather than passing to his wife's family. William ended up taking over James' farm and he moved to Cutchogue late in the summer of 1854, declining to seek re-election for public office for several years.

William married Sarah Elizabeth Havens on July 1, 1857 in Southold, New York and they had three children together, James, William and Julia. Sarah was a woman of royal pedigree, thanks to her four times great grandfather, Arthur Bostwick, who emigrated to Stratford, Connecticut from Tarporley, Cheshire County, England during the early 1600s. Arthur was a descendent of the Bostock family who modified his last name to Bostwick, apparently to disassociate himself with family members in the slave trade. The Bostocks, whose best known descendent is Sarah's tenth cousin Thomas Jefferson, were members of the minor gentry who held the title Lord of Bostock and lived in a small village of this name in an area just south-east of Liverpool. The Bostock line can be traced back to 1080, when a certain Osmer, believed to be a Saxon mercenary in the employ of William the Conqueror who was awarded a tract of land for his services, is listed in the famous Domesday Book as the owner of Bostock. There is some debate if Osmer was truly an ancestor, but within several generations a line of descent was clearly established for the Bostocks, with one of the more notable marriages being to Hawise, Countess of Lincoln in her own right, widow of Sir Roger de Quenci and daughter of Hugh de Kevelioc, Palatine Earl of Chester and great-great grandson of King William the Conqueror. Over the generations, the various Bostock lords participated in many of the key events in English history, including the battles of Shrewsbury and Agincourt. During the War of the Roses, Adam Bostock, knight and Lord of Bostock, was slain in battle and his son was poisoned. Many of the families they married into had distinguished pedigrees, making it possible to trace back the family tree via a royal Welsh bloodline to the year 314 AD, the time of the Roman empire. Through her Bostock ancestry, Sarah was a distant cousin of numerous U.S. presidents besides Jefferson, including Washington, Grant, and both Roosevelts, plus many British leaders such as King Henry VIII.

William's daughter Julia (see her) became an important Impressionist painter of the Peconic School on the North Fork of Long Island. The Peconic School, largely inspired by Impressionism in France, though it had other influences, was utterly distinct from the better known Abstract Expressionism movement on the South Fork. The Peconic School included the likes of Benjamin Rutherfurd Fitz, Arthur Henry Prellwitz, and Irving Ramsey Wiles. Julia's works were mainly oil paintings of colorful waterfront scenes around her native home of Cutchogue (see her painting Long Island Beach Scene). She attended Mount Holyoke College from 1884 to 1887, and studied with painters Edward August Bell in Peconic, New York, and Birge Harrison and John Carlson in Woodstock, New York. She also traveled with her close friend Caroline M. "Dolly" Bell and the others to paint in Gloucester, Massachusetts. Lacking the formal art education of some of her peers, she is considered a "non-academic" whose works might be a little less masterful, though they have stood the test of time. She frequently exhibited her paintings in New York City at places like the Pen and Brush Club.

On February 19, 1881, William returned from Riverhead on the evening train and was walking from the station to his residence, when he slipped on some ice and fell, slightly cutting the palm of his hand on what he thought was a twig or root. The cut became swollen and inflamed, but he continued to write and consult, until suddenly symptoms of lockjaw ensued. Despite getting top notch medical attention, he died on February 27th. A local paper, the Long Island Traveler, noted that William was "the best known man in Suffolk County" who "was a great friend of the poor man and espoused his cause as gladly as he did that of his wealthy clients."

The paper concluded, "Truly, he was a good man, and we have met with a great public loss."