Manuel Puig has been most prominently noted for his novels, which make use of experimental narrative techniques and include extensive references to popular cultural genres such as classic Hollywood movies and various forms of popular fiction (including the serial, romance, and detective novel). Puig's success as a novelist is indicated, according to Jonathan Tittler, by "the broad dissemination of his works" which resulted in "considerable financial success and artistic independence."

"The name of Manuel Puig has for almost 25 years brought with it associations with popular and mass culture," Tittler claims, noting that while "widely recognized as an innovator of narrative technique," Puig was early on criticized for his blatant use of mass-cultural genres and references: "He was for many years mistakenly viewed as either a parodist of vulgar, mass-produced cultural products or a victim and purveyor of bad taste." Pamela Barcarisse also makes note of a general dismissal of Puig on the part of critics, stating that "the fact is that none of Puig's novels has been immune to adverse criticism; this has ranged from a total lack of understanding in the late sixties to expressions of disappointment, condemnation, even antagonism, in more recent years." Tittler points out that later critics began to interpret Puig's pop-cultural references in greater depth: "Only recently has literary criticism come to … appreciate the depth of his ambivalence about melodrama and the extent of his commitment to subverting structures of authority, in whatever guise they might appear." Barcarisse also makes note of the generally celebratory tone of more recent criticism of Puig's work, stating that "it is gratifying to note that at the present time some journalists and many academic commentators are beginning to take the entire corpus of his writings very seriously indeed, the latter classifying him as one of Latin America's first postmodern authors and by far the most impressive representative of the Latin American Post-Boom. Indeed, there is little to complain about in current Puig criticism." Tittler contends that "Puig's writing as a whole fleshes out surprising depth from a world of pure surface" and goes on to note the importance of Puig's influence on the Latin American novel, particularly in terms of his references to mass-cultural forms of media: "In breaking through to a postmodern, culturally unpretentious space … Puig made an impact that was so immense that soon such leaders as Cortazar, Vargas Llosa, and Donoso were producing fictions based on movie stars … melodramatic soap operas … detective novels … and erotic mysteries." Lucille Kerr notes the impact of Latin American fiction, as influenced by Puig, on international literature, stating, "Puig's work exemplifies modern Latin-American writing's most adventurous contribution to contemporary literary trends, which include a return to popular culture." Kerr describes the combined influence of Puig's experimental narrative style and his references to popular culture, asserting that "Puig's writing challenges conventional notions of literature and art as it draws on literary, subliterary, and nonliterary forms and languages to fashion new narrative models and radical ways of thinking about fiction." Kerr also makes note of Puig's concern with political issues, as expressed through his fiction: "Puig's novels are works of literary experimentation as well as social and cultural criticism."

Puig's first novel began as a set of notes for what he intended as a film script; however, Puig eventually realized that it was turning into what became his first published novel, La traicion de Rita Hayworth (translated as Betrayed by Rita Hayworth), published in 1968. Loosely autobiographical, Puig's novel makes use of experimental narrative techniques in focusing on a boy who grows up in an Argentine town in the pampas. The title refers to the role of escapist fantasy that classic Hollywood movies play in the lives of the novel's provincial characters. His second novel, Boquitas Pintadas (1969; translated as Heartbreak Tango), was based on the genre of the serialized novels, popular in Argentina, which are considered to be non-literary. His third novel, The Buenos Aires Affair (1973), is based on the genre of the detective novel and focuses on the sexual obsessions of the characters.

First published in 1976, Puig's fourth novel, Kiss of the Spider Woman, was banned in Argentina until 1983, when a change in government resulted in greater tolerance. Tittler has stated that Kiss of the Spider Woman, "widely considered his greatest work," is also "Puig's most generally successful novel because it is, far and away, his most powerful." Tittler also notes that it is "an uncommonly good read." Kerr points out the political implications of this novel: "The success of [Kiss of the Spider Woman] clearly speaks not only of the power of Puig's fiction and style but also of the public's interest in the issues about which he chose to write."

Puig's final novel, Tropical Night Falling, was first published in Spanish in 1988, and then published in English translation in 1991, after his death.