After booking the first film she auditioned for, a small but pivotal role in Walk the Line, romantically opposite Joaquin Phoenix, Grant continued to star in several independent films while earning her BFA in Theater Performance at the University of Memphis before moving to Los Angeles. While in Memphis, she met Director Craig Brewer who cast her as the lead in two of his indie films before casting her in the film Black Snake Moan as Christina Ricci's best friend, while alongside fellow Memphian Justin Timberlake, and later as the lead in his MTV series $5 Cover. She then played the lead role of Megan Graves in comic book Writer Brian Pulido's first independent feature film The Graves, followed by the role of Beverly in the film Joshua Tree, 1951: A Portrait of James Dean, directed by Matthew Mishory. In 2013, Grant played the lead role of Martha Collins in the film The Insomniac, directed by Monty Miranda, and voiced Black Widow in the Marvel Animation movie Iron Man: Rise of Technovore. In 2015, Clare played a supporting role in the award winning film by Antonia Bogdanvich, produced by Peter Bogdanovich, Phantom Halo and is starring in a holiday anthology movie, her segment directed by Scott Stewart, called Holidays is the virtual reality segment of the anthology for Christmas, which was a featured selection of the 2016 Tribeca Film Festival. In 2016 she filmed the indie movies "Hanky Panky" and "Dance, Baby, Dance!". Most recently Clare starred in the film Changeland alongside Seth Green who wrote, directed and also starred in the film.

In October 2006, after her role in Masters of Horror: Valerie on the Stairs, she appeared as "Babe of the Month" in a non-nude pictorial in Playboy magazine.

Under their company Danger Maiden Productions, Grant began her producing endeavors with her partner Rileah Vanderbilt, with their viral online series Saber, winning them two awards at the 2009 Star Wars Fan Film Awards: Best Action and Audience Choice awards. In 2010, the duo began working with Milynn Sarley & Michele Boyd to create the online series Team Unicorn. In its first week alone, the team’s first project, G33k & G4m3r Girls, a parody of Katy Perry's California Gurls video, achieved over one million views. Stirring much controversy over its sexy portrayal of the women, G33k & G4m3r Girls is a "love letter" written by the girls that pays tribute to their shared mutual passion of Gaming, manga, and science fiction. Grant continues to create viral videos with Danger Maiden / Team Unicorn, including "All About that Base", a parody video using a Star Wars theme to the hit song by Meghan Trainor. She guest-starred in the second season of the Jane Espenson-scripted romantic comedy web series Husbands and has also guest starred on popular geeky webseries such as The Guild, Save the Supers, Q.V.G., and Tabletop. In 2013, Grant starred as Mala in the Wonder Woman short that achieved over 3 million views in 24 hours, which stars Vanderbilt as Wonder Woman.

Grant first met actor Seth Green in 2006 at the Golden Apple Comics. They married on May 1, 2010 at Skywalker Ranch; the ceremony was officiated by Grant's long-time friend and Director, Craig Brewer.

In 2013, Adult Swim announced that Grant co-created and will be starring in and executive producing a pilot based on the webseries she co-created, Team Unicorn.