Wiltshire was born in London, England, in 1974 to West Indian parents, His father, Colvin was a native of Barbados, and his mother, Geneva, is a native of St. Lucia. Wiltshire was mute when young. At the age of three, he was diagnosed as autistic. The same year, his father died in a motorbike accident.
At the age of five, Stephen was sent to Queensmill School in London where he expressed interest in drawing. The instructors at Queensmill School encouraged him to speak by temporarily taking away his art supplies so that he would be forced to ask for them. Stephen responded by making sounds and eventually uttered his first word—"paper." He learned to speak fully at the age of nine. His early illustrations depicted animals and cars; he is still extremely interested in American cars and is said to have an encyclopedic knowledge of them. When he was about seven, Stephen became fascinated with sketching landmark London buildings. After being shown a book of photos depicting the devastation wrought by earthquakes, he began to create detailed architectural drawings of imaginary cityscapes. He began to communicate through his art. His teachers encouraged his drawing, and with their aid Wiltshire learned to speak at the age of five. At the age of eight, he started drawing imaginary post-earthquake cityscapes and cars. When he was ten, Wiltshire drew a sequence of drawings of London landmarks, one for each letter, that he called a "London Alphabet".
In 1987, Wiltshire was part of the BBC programme The Foolish Wise Ones. Drawings, a collection of his works, was published that same year.
Between 1995 and his graduation in 1998, Wiltshire attended the City and Guilds of London Art School in Kennington, Lambeth, South London.
Wiltshire can look at a subject once and then draw an accurate and detailed picture of it. He frequently draws entire cities from memory, based on double, brief helicopter rides. For example, he produced a detailed drawing of four square miles of London after a single helicopter ride above that city. His nineteen-foot-long drawing of 305 square miles of New York City is based on a single twenty-minute helicopter ride. He also draws fictional scenes, for example, St. Paul's Cathedral surrounded by flames.
Wiltshire's early books include Drawings (1987), Cities (1989), Floating Cities (1991), and Stephen Wiltshire's American Dream (1993). His third book, Floating Cities (Michael Joseph, 1991), was number one on the Sunday Times bestseller list.
In 2003, a retrospective of his work was held in the Orleans House gallery in Twickenham, London.
In May 2005 Stephen produced his longest ever panoramic memory drawing of Tokyo on a 32.8-foot-long (10.0 m) canvas within seven days following a helicopter ride over the city. Since then he has drawn Rome, Hong Kong, Frankfurt, Madrid, Dubai, Jerusalem and London on giant canvasses. When Wiltshire took the helicopter ride over Rome, he drew it in such great detail that he drew the exact number of columns in the Pantheon.
In October 2009 Stephen completed the last work in the series of panoramas, an 18-foot (5.5 m) memory drawing of his "spiritual home", New York City. Following a 20-minute helicopter ride over the city he sketched the view of New Jersey, Manhattan, the Financial District, Ellis Island, the Statue of Liberty and Brooklyn over five days at the Pratt Institute college of art and design in New York City.
In 2010, he made a series of drawings of Sydney, and visited Bermuda National Gallery where the sale of his drawing of Hamilton broke auction records. In June 2010, Christie's auctioned off an oil painting of his "Times Square at Night".
Wiltshire started a tour of China in September 2010, with a first project taking him to Shanghai.
A 2011 project in New York City involved Wiltshire's creation of a 250-foot (76 m) long panoramic memory drawing of New York which is now displayed on a giant billboard at JFK Airport. It is a part of a global advertising campaign for the Swiss bank UBS that carries the theme "We will not rest", The New York Times reported.
In July 2014, Wiltshire drew an aerial panorama of the Singapore skyline from memory after a brief helicopter ride, taking five days to complete the 1 x 4m artwork. The artwork will be presented to President Tony Tan as the Singapore Press Holding (SPH)'s gift to the nation in celebration of Singapore's 50th birthday in 2015, and will be displayed at Singapore City Gallery, visitor centre of the country's urban planning authority, Urban Redevelopment Authority.