The censorship of the film came about as a motion picture ratings system was being considered by the junta-appointed National Legislative Assembly. A replacement for the 1930 film act, the ratings law contained a restrictive ratings structure and retained the government's powers to censor and ban films it deemed would "undermine or disrupt social order and moral decency, or that might impact national security or the pride of the nation". The ratings board would comprise mainly bureaucrats in the Ministry of Culture, as well as members of the Royal Thai Police.

Between Blissfully Yours and Tropical Malady, Apichatpong co-directed The Adventure of Iron Pussy with Artist Michael Shaowanasai, who starred as the main character, a transvestite secret agent, while pop singer Krissada Terrence, better known as Noi from the Thai band Pru, portrayed the male lead. The low-budget, digital movie was a spoof of Thai films of the 1960s and 1970s, particularly the musicals and action films of Mitr Chaibancha and Petchara Chaowarat. The Adventure of Iron Pussy was screened at the Berlin Film Festival in 2004. When asked about the film in May 2013, Apichatpong said: "I have had enough of Iron Pussy for now. I was having a good time making it but I was not inspired."

Apichatpong attended Khon Kaen University and received a bachelor's degree in architecture in 1994. He made his first short film, Bullet, in 1993. He attended the School of the Art Institute of Chicago and received a master's degree of fine arts in filmmaking in 1997.

Apichatpong's feature-length debut, Dokfa nai meuman (Mysterious Object at Noon) is a documentary and was conceptually based upon the "exquisite corpse" game invented by surrealists. He co-founded the production company, Kick the Machine, in 1999, and uses the company as a vehicle for his own works, alongside Thai experimental films and video. The list of other founders includes Gridthiya Gaweewong and Suaraya Weerasethakul and the company co-organised the Bangkok Experimental Film Festival in 1999, 2001, 2005 and 2008.

Apichatpong's 2002 film Sud Sanaeha (Blissfully Yours) was his debut narrative feature film and was awarded the Un Certain Regard prize at the 2002 Cannes Film Festival. His 2004 Sud Pralad (Tropical Malady) won a Jury Prize from the same festival.

The Thai Office of Contemporary Art and Culture also honoured Apichatpong with its 2005 Silpathorn Award for filmmaking. The annual award is given to living contemporary artists in various disciplines.

In 2006, Apichatpong released a feature film, Syndromes and a Century, that was commissioned by Peter Sellars for the New Crowned Hope Festival in Vienna to celebrate the 250th anniversary of Mozart's birth. It premiered at the 63rd Venice Film Festival and screened at numerous film events, such as the 2006 Toronto International Film Festival.

A protest against the draft ratings law was held outside the Parliament building in Bangkok, at which Apichatpong and fellow Thai Directors Wisit Sasanatieng and Pen-Ek Ratanaruang held banners that read: "No Freedom. No Democracy. No Peace" The ratings law, with the "cut-and-ban" categories left intact, was passed on 20 December 2007.

The first English-language book on Apichatpong was published in March 2009. James Quandt is the Editor and author of the analytical career overview that introduces the book. Other contributors include the cultural and political theorist Benedict Anderson, filmmaker Mark Cousins, art curator Karen Newman, critics Tony Rayns and Kong Rithdee, and Actress Tilda Swinton.

In 2010 Apichatpong's feature film, Uncle Boonmee Who Can Recall His Past Lives, won the Palme d'Or at the Cannes Film Festival. The film was also selected as the Thai entry for the Best Foreign Language Film at the 83rd Academy Awards but it did not make the final shortlist.

In 2012, Apichatpong's film Mekong Hotel was screened in the Special Screenings section at the 2012 Cannes Film Festival.

In a May 2013 interview for the Encounter Thailand journal, Apichatpong stated that all of his films are personal in nature and he does not consider himself a cultural ambassador for Thailand. In relation to the concept of "queer", he explained: "For me, the word queer means anything’s possible."

In March 2014, it was announced that Apichatpong will feature among 32 Directors from four continents, including Vincent Gallo and Gaspar Noé, to direct Short Plays, a soccer-themed omnibus production shot around the world. Apichatpong's short is set in his home town, features 22 shots of its lake, almost the only recognizable feature from his childhood, which are arranged like players in a soccer game.

Currently, Apichatpong has finished the script for his upcoming film, Memoria, which will be shot in the country of Colombia in 2019.