The film was shot in the summer and early autumn of 1966 in various rooms and locations inside the Hotel Chelsea, though contrary to the film's title, only poet René Ricard actually lived there at the time. Filming also took place at Warhol's studio The Factory. Appearing in the film were many of Warhol's regulars, including Nico, Brigid Berlin, Gerard Malanga, Mary Woronov as Hanoi Hannah, Ingrid Superstar, International Velvet and Eric Emerson. According to Burns' documentary, Warhol and his companions completed an average of one 33-minute segment per week.

Roger Ebert reviewed the film in June 1967, and had a negative response to it, granting it one star out of four. In his review of the film, he stated, "what we have here is 3½ hours of split-screen improvisation poorly photographed, hardly edited at all, employing perversion and sensation like chili sauce to disguise the aroma of the meal. Warhol has nothing to say and no technique to say it with. He simply wants to make movies, and he does: hours and hours of them." Variety wrote that the film was "a pointless, excruciatingly dull three-and-a-half hours spent in the company of Andy Warhol's friends."

While the film is unavailable for personal purchase, it is often screened at art museums, and has been shown at The Museum of Modern Art (which owns a rare print of the film reels) as well as The Andy Warhol Museum in Pittsburgh, Pennsylvania. The film was screened in San Francisco for the first time in nearly twenty years at Castro Theatre in April 2002. Screenings were also held in 2010 at the Seattle Art Museum and at the Varsity Theater in Chapel Hill, North Carolina, and in 2011 at the High Museum of Art in Atlanta, Georgia.

Chelsea Girls is largely unavailable for home video format. The film belongs to the Andy Warhol Foundation, and it, along with Warhol's other films (apart from a handful of his screen tests, which have since been released on DVD) have never seen home video releases in the United States. In Europe, however, a handful of Warhol's films were released on DVD, including a short-lived DVD print of Chelsea Girls which was available in Italy for some time. This Italian DVD print, which is the film's only official home video release, was released on September 16, 2003.

Although the film garnered the most commercial success of Warhol's films, reaction to it was mixed. As of September 2017, the film review aggregator Rotten Tomatoes has the film ranked as 50% "Rotten", or negative, out of ten collected reviews. Of the "Top Critics" reviews, 2 of the 5 (40%) are positive. In the UK, it was refused a theatrical certificate in 1967 by the British Board of Film Classification.