He is a supporter of various veterans' organizations and founded the Lt. Dan Band (named after his character in Forrest Gump), which plays at military bases around the world.

Sinise's acting career started on stage with the Steppenwolf Theatre Company in 1983, when he directed and starred in a production of Sam Shepard's True West for which he earned an Obie Award.

Sinise received an Academy Award nomination for Best Supporting Actor for his portrayal of Lieutenant Dan Taylor in Forrest Gump (1994).

Sinise is widely known for his leading role as Detective Mac Taylor in the long-running CBS series CSI: NY (2004–13).

In 1974, Sinise and two friends, Terry Kinney and Jeff Perry, founded the Steppenwolf Theatre Company in Chicago, Illinois.

In 1983, he earned an Obie Award for his direction, and a year later appeared with John Malkovich in the PBS' American Playhouse production of the play.

In 1988, Sinise directed Miles from Home, a film starring Richard Gere, about two brothers' fight against the foreclosure of the family farm.

In 1992, Sinise starred in the film adaptation of John Steinbeck's classic novel Of Mice and Men, which he also directed and produced.

Subsequent roles include Lieutenant Dan Taylor in Forrest Gump (1994), for which Sinise was nominated for the Academy Award for Best Supporting Actor.

He has also appeared in Ron Howard's Apollo 13 (1995), Ransom (1996), Snake Eyes (1998), Frank Darabont's The Green Mile (1999), Reindeer Games (2000), Mission to Mars (2000), and Impostor (2002).

Sinise has collaborated with fellow actor Tom Hanks three times, in Forrest Gump, Apollo 13, and The Green Mile.

In 2004, Sinise began his first regular television series, in the crime drama CSI: NY, in which he plays Detective Mac Taylor.

Several episodes have allowed Sinise to demonstrate his musical prowess, including a season-two episode where Mac Taylor plays the bass guitar in a jazz club with musicians Kimo and Carol Williams and Danny Gottlieb, members of the Lt. Dan Band, which Sinise and Kimo Williams co-founded in 2003.

Apart from his television and film work, Sinise has served as the host in the video for the Epcot ride Mission: SPACE at Walt Disney World, Orlando, Florida, and as a model for Baume & Mercier watches.

Also in 2009, Sinise lent his voice talents in the Thomas Nelson audio Bible production known as The Word of Promise, playing the character of David.

[15][16] On October 30, 2017, Sinise was selected as Grand Marshal of the Pasadena Tournament of Roses Parade, which took place on January 1, 2018.

[25][26] In 2006, Sinise began co-hosting the National Memorial Day Concert on the Mall in Washington, D.C., with actor and Illinois native Joe Mantegna.

Each year the foundation raises over $30 million which it uses to benefit military veterans, including building smart homes for those who are disabled.

[31][32] In 2019, a video went viral of Gary Sinise reacting to a video of active duty service men and women, veterans, first responders, their families, and Colin Powell, Tom Hanks, Robert De Niro, Ron Howard, Steve Buscemi, Jay Leno, Tim Allen, Rob Lowe, Judd Apatow and Robin Roberts giving thanks to Sinise for all his humanitarian work.

[45][46] Sinise's name was in an advertisement in the Los Angeles Times (August 17, 2006) that condemned Hamas and Hezbollah and supported Israel in the 2006 Israel-Lebanon conflict.

[47] In May 2009, Nicolle Wallace, a former adviser to George W. Bush and John McCain, mentioned Sinise as a potential Republican presidential candidate in 2012.