He was greatly frustrated with the journalist work that he found at the time, later saying, "[I couldn't find] a job writing very hard-hitting, interesting pieces that would really make some sort of difference.

"...I sort of decided to forget it and just go the other route, which was basically take my hobby, which has been cartooning, and see if I could make a living out of that," he later told the BBC.

[10] This job provided the opportunity for him to create and edit another satire: the comics anthology Centrifugal Bumble-Puppy[11][2] (a name he took from an overcomplicated children's toy in Aldous Huxley's Brave New World), published by The Comics Journal's parent company Fantagraphics Books.

In 1988, he left the U.S. again to travel across Europe, a trip which he chronicled in his autobiographical comic Yahoo (also published by Fantagraphics).

[12] The Gulf War segment of Yahoo drew Sacco into a study of Middle Eastern politics, and he traveled to the Occupied Palestinian territories to research his first long work.

[13] Sacco next travelled to Sarajevo and Goražde near the end of the Bosnian War, and produced a series of reports in the same style as Palestine: the comics Safe Area Goražde, The Fixer, and the stories collected in War's End; the financing for which was aided by his winning of the Guggenheim Fellowship in April 2001.

He has also contributed short pieces of graphic reportage to a variety of magazines, on subjects ranging from war crimes to blues, and was a frequent illustrator of Harvey Pekar's American Splendor.

In 2009, his Footnotes in Gaza was published, which investigates two forgotten massacres that took place in Khan Younis and Rafah in November 1956.

[16] His latest work is Paying the Land (2020) discussing climate change and the indigenous Dene community of Northwest Canada, who, he says, were subject to cultural genocide by means of compulsory residential schooling, treaties, and capitalism.

[24] Joe Sacco was awarded the degree of Doctor of Literature (Honoris Causa) by the University of Malta on November 17, 2023.