In the 1990s, Cusack starred in leading roles in each films, including Bullets Over Broadway (1994), Con Air (1997), Grosse Pointe Blank (1997), The Thin Red Line (1998), Being John Malkovich (1999), High Fidelity (2000), America's Sweethearts (2001), Max (2002), and Runaway Jury (2003).

[12] On the set of Grandview, U.S.A. (1984), his co-star Jamie Lee Curtis gifted Cusack with his first car, a 1974 Chevrolet Impala, which she had named 'La Bamba'.

[17] Cusack then had a brief appearance in Rob Reiner's Stand by Me (1986) as the older brother of Gordie, a film based on Stephen King's The Body.

"[18] In 1988, Cusack went on and starred in the Independent film Eight Men Out (1988), about Major League Baseball's Black Sox Scandal during the 1919 World Series.

[22] In the film, Cusack became known for the infamous boombox scene, in which his character Lloyd stands near Diane's bedroom window, and wordlessly holds up a cassette player above his head, blasting Peter Gabriel's 1986 song "In Your Eyes".

[28] Released in the same year, Cusack also starred in the Nicolas Cage film Con Air (1997) as the FBI agent Vince Larkin,[29] and in Clint Eastwood's Midnight in the Garden of Good and Evil (1997).

[31] The film was nominated for three Academy Awards, including Best Director (Jonze), Best Original Screenplay (Charlie Kaufman) and Best Supporting Actress (Catherine Keener).

[32] Cusack was nominated for a Golden Globe Award for Best Actor – Motion Picture Musical or Comedy for his performance in High Fidelity (2000),[33] based on Nick Hornby's novel about Rob, a record store owner, and the history of his failed relationships.

[34] In the early 2000s, Cusack appeared in a few romantic comedies such as America's Sweethearts (2001), Serendipity (2001), Must Love Dogs (2005), playing opposite lead actresses Julia Roberts, Kate Beckinsale, and Diane Lane.

In Roland Emmerich's epic disaster film 2012 (2009), Cusack starred as Jackson Curtis, a struggling novelist who attempts to save his family during a global cataclysm.

[46] This era was a new peak in his career,[47] however, in 2014, Cusack infamously criticized Hollywood saying the mega-corporations have stepped in with 50-producer movies, franchises are king, and stars are used as leverage.

"[48] Later, Cusack starred in video on demand films, including The Factory (2012), The Numbers Station (2013), The Frozen Ground (2013), Grand Piano (2013), Drive Hard (2014), The Prince (2014), Reclaim (2014), Cell (2016), Arsenal (2017), Blood Money (2017), and Singularity (2017).

Phil Hoad of The Guardian highlighted the movie's engaging narrative and cultural commentary, mentioning Cusack's role as part of the ensemble cast.

He voiced his opposition to the war in Iraq and Bush's administration, calling the government's worldview "depressing, corrupt, unlawful, and tragically absurd".

In June 2015, he stated in an interview with The Daily Beast that "when you talk about drones, the American Empire, the NSA, civil liberties, attacks on journalism and whistleblowers, [Obama] is as bad or worse than Bush".

[56][57] At a Moscow hotel room in 2015, Cusack, Daniel Ellsberg, and Arundhati Roy met Edward Snowden, who had fled the US because of his leaks of classified information surrounding illegal population surveillance.

[62] During May 2020, Cusack was recording a George Floyd protest in Chicago on social media when he was attacked by police with batons and later pepper-sprayed.

Maybe being outspoken hurts your career… I’m just aware it helps me sleep better at night, knowing that I wasn’t passive during this time.Cusack has been fiercely critical of Israel's military actions against Palestinians.

[65] Cusack signed an open letter in support of Lorde cancelling performances in Israel, which was in response to a request from the BDS movement.

[66] Following the 2023 Hamas-led attack on Israel and the Israeli invasion of the Gaza Strip, Cusack signed another open letter (Artists4Ceasefire) urging Joe Biden to "call for and facilitate a ceasefire without delay..."[67] He also blocked and direct messaged pro-Israel and Zionist Twitter users insults, and asserted that Israel is conducting a genocide in Gaza.

[68] In June 2019, Cusack tweeted out an image of a large fist with a blue Star of David crushing a small crowd of people next to a quote by neo-Nazi Kevin Alfred Strom often misattributed to Voltaire: "To learn who rules over you, simply find out who you are not allowed to criticize".