Her other notable films include The Sisterhood of the Traveling Pants 2 (2008), Conan the Barbarian (2011), Alex Cross (2012), Raze (2013), and Inside (2016).

[4] Nichols said in an interview that, when she was in high school, her mother would euphemistically refer to her as "a late bloomer", "which meant that I had uncontrollable arms and legs, I had very long appendages.

She later said she had "never really done a proper audition before", and added that "I had such fun [filming on set], that day actually made me want to pursue [acting] more seriously.

"[11] Later that year she was cast in her first major film role as Jessica, a dogged student newspaper reporter, in Dumb and Dumberer: When Harry Met Lloyd (2003).

The series premiered in June 2005 and critical reception was mixed; it had been scheduled opposite the popular Dancing with the Stars on ABC, and due to low ratings six of the 13 produced episodes were aired.

[27] Nichols had a small part in the drama film Resurrecting the Champ (2007), playing the assistant to a sportswriter (Josh Hartnett) who believes he has found a former boxing legend (Samuel L. Jackson) living homeless on the streets.

[29] Her first starring film role was in the 2007 horror–thriller P2, as a businesswoman who becomes trapped inside a public parking garage with a deranged security guard.

"[33] John Anderson of Variety wrote that "Nichols is in territory well trod over the years by everyone from Fay Wray and Grace Kelly to Heather Langenkamp, the terrified but gutsy heroine, who in this case has been chloroformed and put into a sheer white evening dress by her abductor—who must have anticipated that his captive would try to escape in an elevator, which he could then fill with water.

"[34] Nichols had a supporting role in The Sisterhood of the Traveling Pants 2 (2008), playing a jealous friend of America Ferrera's character.

"[36] Stephen Holden, writing for The New York Times, similarly said, "It falls to Ms. Nichols to play the movie's designated blond baddie, a cold, arrogant vixen who tries to undermine [Ferrera's character's] triumphs in romance and onstage.

"[40] She put on approximately 15 pounds (6.8 kg) of muscle for the role and trained in mixed martial arts with co-star Sienna Miller for some of the film's action sequences.

[43] Richard Corliss of Time wrote that Nichols had "an appealing manner and comely biceps" as Scarlett O'Hara and took notice of her "savory girl fight with Sienna Miller, as the mostly villainous Baroness.

Joe, Nichols' next project was the horror film For Sale by Owner, where she played the half of a newly wed couple buying a house with a secret past.

Nichols starred as a police detective assigned to investigate the murder of a young boy in the small-scale crime drama Meskada (2010), which premiered at the Tribeca Film Festival and received a limited theatrical release in North America.

[51] Boston Globe felt that Nichols portrayed her "pure-blooded innocent" character with the "enthusiasm of a bored office receptionist".

[55] Nichols next starred in the independent romantic comedy A Bird of the Air (2011) as "a librarian who joins a highway patrolman to uncover the mysteries behind the cryptic sayings spoken by an ancient parrot.

[58] The New York Times remarked that the actress "is consistently appealing in the kind of role Zooey Deschanel has pretty much cornered",[59] while the Village Voice found her character to be a "grating twit".

Nichols starred opposite Tyler Perry in the thriller Alex Cross (2012), as the blighted colleague of a psychologist and police lieutenant.

Like Conan, her previous wide release, the film garnered negative reviews,[63] and made a lackluster US$34.6 million worldwide.

[64] In the independent exploitation film Raze (2013), she appeared opposite Zoë Bell as women forced to fight against each other for the twisted entertainment of the wealthy elite.

[65] Nichols is credited as an executive producer in the film, and was drawn to the project for its female "empowering" message, remarking: "Give us a challenge and we'll meet it.

[66] She next starred with Nicolas Cage in the action thriller Rage (2014), as the wife of a reformed criminal seeking his own brand of justice after their daughter gets kidnapped.

[67] In 2014, she made a one-episode appearance in the Lifetime series Witches of East End and debuted in a recurring arc in USA Network's Rush.

The following year, she obtained a recurring role as a "problem employee at the law firm she works at" in the fourth season of Chicago Fire.

The film was released for selected theaters and VOD,[69] and in its review, The Hollywood Reporter remarked that Nichols "attempts to adopt an attitude somewhere between shell-shocked survivor and sympathetic physician, but doesn't manage to fulfill the role's potential".

[72] Nichols next obtained another recurring role on television as a former guardian who has been thrust back five centuries into the past to finally move forward, in the fourth season of the TNT fantasy series The Librarians.

[73] In 2019, Nichols had a five-episode run as Martha Stroud, a Gestapo bodyguard, on the fourth season of the alternate history series The Man in the High Castle.

Nichols allowed her hair to return to its natural blond color for the ceremony, as it had been dyed red for her consecutive roles in Star Trek and G.I.