In 1992 he won a scholarship that allowed him to travel to Zimbabwe. Ofili studied cave paintings there, which had some effect on his style.

Between 1995 and 2005, Ofili focused on a series of watercolors, each about 9½ by 6½ inches and produced in a single sitting. They predominantly feature heads of men and women, as well as some studies of flowers and birds. Ofili’s paintings also make reference to blaxploitation films and gangsta rap, seeking to question racial and sexual stereotypes in a humorous way. In a series of faces that Ofili called Harems, each arrangement consists of one man with as many as four women on each side of him.

Ofili’s work was featured in a museum in the 1995 exhibition Brilliant! New Art from London at the Walker Art Center. Significant solo exhibitions include the Arts Club of Chicago (2010), Kestnergesellschaft, Hanover (2006), the Studio Museum in Harlem, New York (2005), and Southampton City Art Gallery (1998). In 2010, Tate Britain presented the most extensive exhibition of his work to date. In 2014, The New Museum in New York presented the first, major solo show of Ofili’s work in the U.S. titled Chris Ofili: Night and Day.

Ofili was established through exhibitions by Charles Saatchi at his gallery in north London and the travelling exhibition Sensation (1997), becoming recognised as one of the few British artists of African / Caribbean descent to break through as a member of the Young British Artists group. Ofili has also had numerous solo shows since the early 1990s, including at the Serpentine Gallery. In 1998, Ofili won the Turner Prize, and in 2003 he was selected to represent Britain at the Venice Biennale of that year, where his work for the British Pavilion was done in collaboration with the architect David Adjaye.

His Orgena, a glittery portrait of a black woman created by the artist for his Turner Prize-winning exhibit at the Tate in 1998 was sold to an American collector for a record GBP 1.8 million, over its GBP 1 million high estimate, at Christie’s London in 2010. In 2015, art collector David Walsh sold Ofili’s 8-foot-tall The Holy Virgin Mary for 2.9 million pounds at Christie’s.

One of his paintings, The Holy Virgin Mary, a depiction of the Virgin Mary, was at issue in a lawsuit between the mayor of New York City, Rudy Giuliani, and the Brooklyn Museum of Art when it was exhibited there in 1999 as a part of the “Sensation” exhibit. The painting depicted a Black Madonna surrounded by images from blaxploitation movies and close-ups of female genitalia cut from pornographic magazines, and elephant dung. These were formed into shapes reminiscent of the cherubim and seraphim commonly depicted in images of the Immaculate Conception and the Assumption of Mary. Following the scandal surrounding this painting, Bernard Goldberg ranked Ofili No. 86 in 100 People Who Are Screwing Up America. Red Grooms showed his support of the artist by purchasing one of Ofili’s paintings in 1999, even after Giuliani famously exclaimed, “There’s nothing in the First Amendment that supports horrible and disgusting projects!” The painting was owned by David Walsh and was on display at the Museum of Old and New Art in Hobart, Tasmania. Steven A. Cohen then owned it for three years and donated the painting to the Museum of Modern Art.

Ofili visited Trinidad for the first time in 2000, when he was invited by an international art trust to attend a painting workshop in Port of Spain. He permanently moved to Trinidad in 2005. In 2002, he married Roba El-Essawy, former singer with trip-hop band Attica Blues. They divorced in 2019. He maintains a studio in Port of Spain, Trinidad.

After relocating to Trinidad in 2005, Ofili began a series of blue paintings inspired by the Jab Jab or “blue devils” who participate in the Trinidad and Tobago Carnival, and the Expressionist group of German and Russian artists, Der Blaue Reiter. These paintings often employed the use of a silver, acrylic background with layers of dark oil pigment on top. Later iterations of these works were shown at Ofili’s solo show Chris Ofili: Day and Night at The New Museum of New York which were installed in a very dimly lit room, causing viewers to adjust their eyes to the darkness in order to see the paintings.

The Upper Room is an installation of 13 paintings of rhesus macaque monkeys by Ofili in a specially designed room. It was bought by the Tate Gallery in 2005 and caused controversy as Ofili was on the board of the Tate Trustees at the time of the purchase. In 2006 the Charity Commission censured the Tate for this purchase.

Ofili’s early work was heavily influenced by Jean-Michel Basquiat, Georg Baselitz, Philip Guston, and George Condo. Peter Doig was doing graduate work at the Chelsea College of Arts when Ofili was an undergraduate, and they soon became friends. In 2014, art critic Roberta Smith held that Ofili has much in common with painters like Mickalene Thomas, Kerry James Marshall, Robert Colescott and Ellen Gallagher, and with more distant precedents such as Bob Thompson, Beauford Delaney and William H. Johnson.

Ofili was appointed Commander of the Order of the British Empire (CBE) in the 2017 New Year Honours for services to art. Ofili was included in the 2019 edition of the Powerlist, ranking the 100 most influential Black Britons.