The financial and critical success of Carrie allowed De Palma to pursue more personal material. The Demolished Man was a novel that had fascinated De Palma since the late 1950s and appealed to his background in mathematics and avant-garde storytelling. Its unconventional unfolding of plot (exemplified in its mathematical layout of dialogue) and its stress on perception have analogs in De Palma's filmmaking. He sought to adapt it on numerous occasions, though the project would carry a substantial price tag, and has yet to appear onscreen (Steven Spielberg's adaptation of Philip K. Dick's Minority Report bears striking similarities to De Palma's visual style and some of the themes of The Demolished Man). The result of his experience with adapting The Demolished Man was The Fury, a science fiction psychic thriller that starred Kirk Douglas, Carrie Snodgress, John Cassavetes and Amy Irving. The film was admired by Jean-Luc Godard, who featured a clip in his mammoth Histoire(s) du cinéma, and Pauline Kael who championed both The Fury and De Palma. The film boasted a larger budget than Carrie, though the consensus view at the time was that De Palma was repeating himself, with diminishing returns. As a film it retains De Palma's considerable visual flair, but points more toward his work in mainstream entertainments such as The Untouchables and Mission: Impossible, the thematic complex thrillers for which he is now better known.

These traits come to the fore in Hi, Mom!'s "Be Black, Baby" sequence. This sequence parodies cinéma vérité, the dominant documentary tradition of the 1960s, while simultaneously providing the audience with a visceral and disturbingly emotional experience. De Palma describes the sequence as a constant invocation of Brechtian distanciation: "First of all, I am interested in the medium of film itself, and I am constantly standing outside and making people aware that they are always watching a film. At the same time I am evolving it. In Hi, Mom! for instance, there is a sequence where you are obviously watching a ridiculous documentary and you are told that and you are aware of it, but it still sucks you in. There is a kind of Brechtian alienation idea here: you are aware of what you are watching at the same time that you are emotionally involved with it."

An early association with a young Robert De Niro resulted in The Wedding Party. The film, which was co-directed with Leach and Producer Cynthia Munroe, had been shot in 1963 but remained unreleased until 1969, when De Palma's star had risen sufficiently within the Greenwich Village filmmaking scene. De Niro was unknown at the time; the credits mistakenly display his name as "Robert Denero." The film is noteworthy for its invocation of silent film techniques and an insistence on the jump-cut for effect. De Palma followed this style with various small films for the NAACP and The Treasury Department.

After the success of his 1968 breakthrough, De Palma and his producing partner, Charles Hirsch, were given the opportunity by Sigma 3 to make an unofficial sequel of sorts, initially entitled Son of Greetings, and subsequently released as Hi, Mom!. While "Greetings" accentuated its varied cast, Hi, Mom! focuses on De Niro's character, Jon Rubin, an essential carry-over from the previous film. The film is ultimately significant insofar as it displays the first enunciation of De Palma's style in all its major traits – voyeurism, guilt, and a hyper-consciousness of the medium are all on full display, not just as hallmarks, but built into this formal, material apparatus itself.

Dionysus in 69 (1969) was De Palma's other major documentary from this period. The film records The Performance Group's performance of Euripides' The Bacchae, starring, amongst others, De Palma regular william Finley. The play is noted for breaking traditional barriers between performers and audience. The film's most striking quality is its extensive use of the split-screen. De Palma recalls that he was "floored" by this performance upon first sight, and in 1973 recounts how he "began to try and figure out a way to capture it on film. I came up with the idea of split-screen, to be able to show the actual audience involvement, to trace the life of the audience and that of the play as they merge in and out of each other."

In the 1970s, De Palma went to Hollywood where he worked on bigger budget films. In 1970, De Palma left New York for Hollywood at age thirty to make Get to Know Your Rabbit, starring Orson Welles and Tommy Smothers. Making the film was a crushing experience for De Palma, as Tommy Smothers did not like many of De Palma's ideas.

De Palma has been married and divorced three times, to Actress Nancy Allen (1979–1983), Producer Gale Anne Hurd (1991–1993), and Darnell Gregorio (1995–1997). He has one daughter from his marriage to Hurd, Lolita de Palma, born in 1991, and one daughter from his marriage to Gregorio, Piper De Palma, born in 1996. He resides in Manhattan, New York.

For many film-goers, De Palma's gangster films, most notably Scarface and Carlito's Way, pushed the envelope of on-screen violence and depravity, and yet greatly vary from one another in both style and content and also illustrate De Palma's evolution as a film-maker. In essence, the excesses of Scarface contrast with the more emotional tragedy of Carlito's Way. Both films feature Al Pacino in what has become a fruitful working relationship. In 1984, he directed the music video of Bruce Springsteen's song Dancing in the Dark. The 1980s were denoted by De Palma's other films Dressed To Kill, Blow Out, and Body Double.

Later into the 1990s and 2000s, De Palma did other films. He attempted to do dramas and a few thrillers plus science fiction. Some of these movies (Mission: Impossible, Carlito's Way) worked and some others (Raising Cain, Mission to Mars) failed at the box office. However, The Bonfire of the Vanities would be De Palma's biggest box office disaster, losing millions.

A more political controversy erupted in a later movie from De Palma, Redacted (2007), which had the subject of American involvement in Iraq, including the committing of war atrocities there. It received limited release in the United States and grossed less than $1 million.

In 2012, his film Passion was selected to compete for the Golden Lion at the 69th Venice International Film Festival. In 2015, he was the subject of a documentary film, De Palma.

"Be Black, Baby" was filmed in black and white stock on 16 mm, in low-light conditions that stress the crudity of the direct cinema aesthetic. It is precisely from this crudity that the film itself gains a credibility of "realism." In an interview with Michael Bliss, De Palma notes "[Be Black, Baby] was rehearsed for almost three weeks... In fact, it's all scripted. But once the thing starts, they just go with the way it's going. I specifically got a very good documentary camera filmmaker (Robert Elfstrom) to just shoot it like a documentary to follow the action." Furthermore, "I wanted to show in Hi, Mom! how you can really involve an audience. You take an absurd premise – "Be Black, Baby" – and totally involve them and really frighten them at the same time. It's very Brechtian. You suck 'em in and annihilate 'em. Then you say, "It's just a movie, right? It's not real." It's just like television. You're sucked in all the time, and you're being lied to in a very documentary-like setting. The "Be Black, Baby" section of Hi, Mom! is probably the most important piece of film I've ever done."