Early in her career, Kalogridis wrote a spec script about Joan of Arc titled In Nomine Dei. She sold the script to Warner Bros. in April 1994, but a film was not produced. In March 1995, she was a Writer of the early script for X-Men, a blockbuster film released in 2000. In late 1999, she did uncredited work on the script for Scream 3.

In September 2000, she had a screenwriting credit for the 2001 film Lara Croft: Tomb Raider. She was executive Producer and the Writer for episodes "Slick" and "Premiere" in the 2002 series Birds of Prey. In September 2003, she was involved in the rewrite of the Wonder Woman live action film adaptation for Warner Bros. She was Screenwriter for the English language version of the 2004 film Night Watch, and also wrote the script for the 2004 film Alexander.

In January 2005, she worked on a remake of The Lone Ranger for Columbia Pictures. In November 2005, she helped write Borgia, an ImageMovers film about the Borgia family in 15th century Rome. In February 2006 she began writing The Dive, Director James Cameron's planned film about the freediver Francisco "Pipin" Ferraras and his wife Audrey Mestre.

Kalogridis became involved as a peacemaker in the 2007–2008 Writers Guild of America strike, working with Writers and producers to reach a solution. The New York Times reported her involvement, "Ms. Kalogridis and her friends... had become a pipeline to the guild members holding out for sizable gains, whose support would be needed if any deal was to be reached." She is also the founder of the pro-union website Hollywood United.

She was an executive Producer of the 2009 blockbuster Avatar by Director James Cameron. She was executive Producer and Screenwriter of the 2010 film Shutter Island. She produced the 2013 film White House Down. In 2013, she and Patrick Lussier were both named co-writers for the fifth film in the Terminator series, Terminator Genisys, for Paramount Pictures and Skydance Productions. She was also an executive Producer of the 2015 film.

In 2018, she was Producer for the film The House with a Clock in Its Walls. She was also creator, Screenwriter, and executive Producer of Altered Carbon, a Netflix scifi series which premiered in February 2018. She continues to work on the film adaptation of the manga Alita: Battle Angel as a co-writer along with James Cameron and Robert Rodriguez, with a trailer released in December 2017. Since 2016 she has also been writing and executive producing the untitled Sword Art Online live-action series for Netflix. She is writing the pilot, noting in an interview that she was working to not "whitewash" the adaptation.