One of her first roles was as Foxy Fox in the Missoula Children's Theater production of Snow White and the seven Dwarfs staged in Fort McMurray.

[5] In her film debut Species (1995), 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.

Pursued by a team of experts who band together to stop her, she embarks on a killing spree while also discovering her powerful instinct to mate, which would result in her offspring being a threat to mankind.

In 1998, she played Eve, a more ambiguous genetic duplicate of Sil, in Species II, which was a failure at the box office.

[5] A few smaller independent movies followed, including Bela Donna and Dog Park, with varied box-office returns.

Despite having some reservations about the science-fiction genre, she signed up for John Carpenter's Ghosts of Mars (2001) in the lead role of Lieutenant Melanie Ballard.

She guest-starred as a substitute teacher in the first-season South Park episode "Tom's Rhinoplasty", and was credited as "the chick from Species".

[9] She also starred in the expansion set to the video game Command & Conquer 3: Tiberium Wars, entitled Kane's Wrath.

She has also been involved with two other productions, joining the cast of Dave Rodriguez's Anytown, an indie drama that examines a racist high-school attack and its aftermath.

[16] In November 2017, during the height of the #MeToo movement, Henstridge joined six other actresses in accusing director Brett Ratner of sexual assault and harassment; she maintains that he forced her to perform oral sex on him in the early 1990s.