Hamilton's other film credits include Children of the Corn (1984), Black Moon Rising, King Kong Lives (both 1986), Mr. Destiny (1990), Dante's Peak (1997), and The Kid & I (2005).

On television, she starred as Catherine Chandler in Beauty and the Beast (1987–1989) and played the recurring role of Mary Elizabeth Bartowski on NBC's Chuck (2010–2012).

Her first major role came the following year when she appeared as Lisa Rogers on the short-lived CBS soap opera Secrets of Midland Heights (December 1980–January 1981).

She appeared in her first starring film role in the low-budget thriller TAG: The Assassination Game (1982), and co-starred that same year in the made-for-television movie Country Gold.

[13] Her next role was co-starring in James Cameron's science fiction action film The Terminator (1984) as Sarah Connor, a young waitress—and soon-to-be mother of a valiant resistance leader—who finds herself at the center of a nightmarish ordeal when a soldier travels back in time to help her defeat the titular cyborg assassin, sent from the future to execute her.

[15] Critics believed it to be a perfect example of its genre,[16] with some attributing its strength to Hamilton's performance; The Hollywood Reporter wrote that she displayed "tremendous resiliency" as Connor,[17] while Janet Maslin felt she played the part "engrossingly" in her review for The New York Times.

For her performance in the television movie A Mother's Prayer (1995), where she played a widow diagnosed with AIDS, Hamilton received a CableACE Award and a Golden Globe nomination for Best Actress.

[34] After guest-starring in an episode of Frasier, Hamilton played leading roles in two features that were released one week apart in 1997: political thriller Shadow Conspiracy and the big-budget action-adventure film Dante's Peak.

[35] Critics were mostly unimpressed by the film's derivative narrative,[36] but some praised the effects and performances, with Roger Ebert writing in his review for the Chicago Sun-Times, "In Brosnan and Hamilton [the filmmakers] have actors who play for realism and don't go over the top".

Her next project was the Lifetime movie Sex & Mrs. X (2000), where she played a magazine writer who experiences a sexual reawakening when she is assigned to interview an upper-class Parisian madam.

The Los Angeles Times called it an "[intriguing] character study that passes muster on the strength of good performances by [its leads]", adding that Hamilton was both "tough" and "tender" in the part.

Hamilton received praise for her portrayal of the title character, with Jay Reiner of The Hollywood Reporter commenting: There's an inherent risk in reviving a film classic like Laura … [original star] Gene Tierney … left such an indelible impression that any [actress] trying to fill [her] shoes [is] probably going to suffer by comparison.

[41]The following year, Hamilton starred in the small-scale mystery thriller Skeletons in the Closet (2001), subsequently winning a DVD Exclusive Award for Best Supporting Actress.

Writing for Variety, Frank Rizzo said, "[She is] well cast as the recently widowed but hardly mourning proprietress … She takes over the stage with natural assurance and plays this overripe survivor with lusty humor and cunning".

[44] Hamilton reprised the role of Sarah Connor for a second time with a voice cameo in 2009's Terminator Salvation,[45] which grossed US$371 million at the worldwide box office.

[46] In 2010, she joined the cast of NBC's espionage-style comedy series Chuck, playing the recurring role of CIA agent Mary Elizabeth Bartowski.

[47] That same year, she guest-starred in three episodes of the Showtime dark comedy Weeds—as the marijuana supplier for the series' protagonist—and appeared as a "cartoon American cop" in the poorly received Irish film Holy Water.

[50] She then played a fictional U.S. president in the television miniseries Air Force One Is Down (2013), and had recurring roles as a bounty hunter on the Showcase series Lost Girl (2013) and a mentally ill mother on Syfy's Defiance (2014–2015).

In his evaluation of the latter for The Hollywood Reporter, Frank Scheck described it as "awfully loopy", adding, "it's always a pleasure to see Hamilton, even if it's painfully obvious that she's been cast [here] because of the genre resonance she brings to the table".

[58] Writing for Rolling Stone, David Fear felt that she provided the film's "sinew, heart, and soul", and said of her introduction: A truck pulls up, we see boots hit the ground, and there she is: Sarah Connor 1.0, sunglasses on, stoic and iconic as fuck, gunning down a sprinting shape-shifter and employing a rocket launcher for a finishing move.

It's the sort of movie entrance that the character (and the actor) deserves, the kind that prompts spontaneous, uncontrollable cheering in theaters … Her weathered survivor will charitably share the screen with newcomers and old co-stars alike, but from this moment on, Dark Fate is Hamilton's property.

[61] She began appearing as General McCallister on Syfy's Resident Alien in 2021, which IndieWire called a "genre-bending … spry half-hour comedy [series]".

[63] It was announced in June 2023 that Hamilton would join the ensemble of the Netflix mystery-horror series Stranger Things for its fifth and final season—due to air in 2025—as an unspecified character.

Hamilton has described herself politically as a Democrat, but she voted for Republican candidate Arnold Schwarzenegger—her Terminator co-star—in the 2003 California election after his campaign convinced her he was suitable for the job.

[65] While filming Terminator 2: Judgment Day, Hamilton suffered permanent hearing damage in one ear because she had forgotten to put in her earplugs for a scene which called for Schwarzenegger to fire a shotgun inside an elevator.