In the film, the famously villainous De Niro earned laughs as a Mafia don plagued by anxiety; Billy Crystal co-starred as the terrified psychiatrist who unwillingly treats him. Later that year, De Niro returned to drama in the decidedly less commercial Flawless. In 2000, he starred as Fearless Leader in the combined live action/animated The Adventures of Rocky and Bullwinkle, which he also produced, and as a disapproving father-former CIA agent in the comedy Meet the Parents, costarring Ben Stiller and Blythe Danner.

After costarring with Cuba Gooding Jr. in Men of Honor (2000), De Niro headlined 15 Minutes (2001), an action thriller costarring Ed Burns. He also starred alongside Edward Norton, Angela Bassett, and Marlon Brando in The Score (2001).

De Niro entered the restaurant business with the opening of the TriBeCa Grill in 1988 (based on the ground floor of the TriBeCa Film Center). He is also a partner in Nobu, a high-profile Japanese restaurant with branches in New York, London, and Las Vegas, among other cities.

Notoriously private about his personal life, De Niro was married to the actress Diahnne Abbott from 1976 to 1988. The couple had one son, Raphael, and De Niro adopted Abbott's daughter from a previous marriage, Dreena. A lengthy romance with model-turned-restaurateur Toukie Smith produced twin sons, Aaron and Julian, through a surrogate mother. In 1997, De Niro married longtime girlfriend Grace Hightower, a former flight attendant. The couple had a son, Elliott, in 1998. De Niro reportedly filed for divorce in the summer of 1999.