In her movie debut Species, Henstridge played "Sil," a genetically engineered alien/human hybrid created from a message received by SETI, who breaks free from the captivity of a laboratory when her overseers attempt to "euthanize" her. Pursued by a team of experts who band together to stop her before her "Species" multiplies, Sil embarks on a killing spree while also discovering her powerful instinct to mate. Species was an instant hit, raking in $113 Million (USD). Notable for its sexual content, the film won Henstridge the MTV Movie award for "best kiss" for a scene in which her character, while kissing an aggressive would-be suitor, impales his head with her tongue. The movie gave Henstridge a platform to launch her acting career, but most of the following movies she appeared in were not as successful. Species spawned a sequel Species II, in which a male alien was attempting to mate with Eve, a genetic duplicate of Sil. Eve was played as gentle and more docile than the original Sil, creating an air of sympathy for the character who spends the majority of the movie imprisoned in a glass habitat and undergoing painful experiments. The film was a failure at the box office, taking in $19 million (USD) domestically. A few smaller independent movies followed, including Bela Donna and Dog Park, with varied box office returns. She also starred opposite Jean-Claude Van Damme in the action/adventure movie Maximum Risk. Despite having some reservations about the sci-fi genre, she signed up for John Carpenter's Ghosts of Mars in the lead role and reprised her role as Eve in a brief cameo in Species III. Ghosts of Mars was not well-received, with a 21% rating in Rotten Tomatoes. In 2000, she starred in The Whole Nine Yards and its 2004 sequel The Whole Ten Yards.

She has played a number of roles on television, for example in Caracara and The Outer Limits. From 2005 to 2006, Henstridge had a recurring role in the cancelled ABC drama Commander in Chief, which starred Geena Davis as a fictional female U.S. President. She also hosted Mostly True Stories: Urban Legends Revealed on TLC, a show about urban legends. Natasha guest starred in the South Park first season episode "Tom's Rhinoplasty" as a substitute teacher, and was credited as "the chick from Species."

Henstridge was working on the TV show She Spies, prior to its cancellation. She has also completed a TV movie for the Lifetime channel titled Widow on the Hill. In 2006 she filmed the CTV original mini-series Would Be Kings in Hamilton, Ontario, for which she won a Gemini Award. She also starred in the expansion set to the video game Command and Conquer 3: Tiberium Wars, entitled Kane's Wrath. In 2008 Natasha played a role on the new ABC show, Eli Stone. She has also been involved with two new productions, joining the cast of Dave Rodriguez's "Anytown," an indie drama that examines a racist high school attack and its aftermath. Henstridge will play a news anchor covering an attack on an Indian-American boy by two fellow students who videotape the crime. The event forces her to examine the media's post-September 11 role in fueling hate crimes committed by youth. She has also been involved with the production of Should've Been Romeo from American Independent Pictures.

• Let the Game Begin (2009) (completed) .... Angela
• Anytown (2008) (completed) .... Carol Mills
• "Eli Stone" .... Taylor Wethersby (21 episodes, 2008)
       - Owner of a Lonely Heart (2008) TV episode .... Taylor Wethersby
       - Help! (2008) TV episode .... Taylor Wethersby
       - Happy Birthday Nate (2008) TV episode .... Taylor Wethersby
       - The Humanitarian (2008) TV episode .... Taylor Wethersby
       - Should I Stay or Should I Go? (2008) TV episode .... Taylor Wethersby
        (16 more)
• Deception (2008) .... Simone Wilkinson
• Command & Conquer 3: Kane's Wrath (2008) (VG) .... Alexa Kovacs
• "Would Be Kings" (2008) TV mini-series
• "Impact" (2008) TV mini-series .... Maddie Reese
• "Shark" .... Nicolette Ross (1 episode, 2007)
       - Fall from Grace (2007) TV episode .... Nicolette Ross
• "Commander in Chief" .... Jayne Murray (16 episodes, 2005-2006)
       - Unfinished Business (2006) TV episode .... Jayne Murray
       - Happy Birthday, Madam President (2006) TV episode .... Jayne Murray
       - The Elephant in the Room (2006) TV episode .... Jayne Murray
       - Ties That Bind (2006) TV episode .... Jayne Murray
       - The Price You Pay (2006) TV episode .... Jayne Murray
        (11 more)
• Widow on the Hill (2005) (TV) .... Linda Dupree Cavanaugh
• Species III (2004) (V) .... Eve
• "She Spies" .... Cassie McBain (40 episodes, 2002-2004)
       - Remember When (2004) TV episode .... Cassie McBain
       - Wedding of the Century (2004) TV episode .... Cassie McBain
       - Witness Protection (2004) TV episode .... Cassie McBain
       - Stranded (2004) TV episode .... Cassie McBain
       - London Calling (2004) TV episode .... Cassie McBain
        (35 more)
• The Whole Ten Yards (2004) .... Cynthia
• Power and Beauty (2002) (TV) .... Judy Exner