Winstead was born in Rocky Mount, North Carolina, the daughter of Betty Lou (née Knight) and James Ronald Winstead. When she was five, her family moved to Sandy, Utah, a Salt Lake City suburb. Her interest in performing art also began to emerge with interests in ballet and acting. As a girl, Winstead appeared in the Mountain West Ballet's version of The Nutcracker. Hoping to become a ballerina, at the age of eleven, she received the opportunity to study dance in a summer program of the prestigious Joffrey Ballet School in New York City. There, she studied ballet and jazz dance, but decided to also study acting. Winstead ended up appearing on Broadway during Donny Osmond’s successful run of Joseph and the Amazing Technicolor Dreamcoat. She was also a member of the International Children's Choir during her youth and honed her skills performing at her church.

Winstead began her acting career at age 13, guest starring in episodes of the CBS drama series Touched by an Angel and Promised Land, before being cast as Jessica Bennett in the NBC soap opera series Passions, a role she played from 1999 to 2000. She subsequently appeared in the short-lived CBS drama series Wolf Lake (2001–2002), and in the made-for-television film Monster Island (2002). Trying her hand at comedy, Winstead went the independent film route as the Jewish daughter of a large, zany family in the indie feature Checking Out, but her screen time fared better in the more mainstream Disney live-action film Sky High, which was financially and critically successful. She starred as Gwen Grayson, the in-disguise alter ego of the supervillain Royal Pain.

After the exposure Sky High provided, 2006 saw her forge a professional relationship with the creative team of James Wong and Glen Morgan, formerly best known for their memorable contributions to The X-Files. She and her co-star, Ryan Merriman, landed in the path of the grim reaper’s master plan in Final Destination 3. (Winstead also starred with co-lead Ryan Merriman in 2005's The Ring Two.) The film also acts as the first feature she has a lead role in as well as being the highest-grossing film to date that she has had a lead role in. Morgan and Wong wanted to collaborate with her again and convinced her to appear in their sorority slasher Black Christmas, where she once again teamed up with fellow Final Destination castmate Crystal Lowe. They initially wanted her to play the lead, but afraid of being typecast, Winstead would only accept if she were cast in a supporting role. The film fared poorly with critics and viewers alike, but earned her a nomination for Scream Queen at the 2007 Scream Awards. One day, Winstead inadvertently received a chance to lampoon horror scream queens when The Tonight Show host Jay Leno, unaware of who she was, knocked on her front door and included her in a comedy segment spoofing horror movies; She and Riley parodied the Saw series. That same year, she appeared in Emilio Estevez's Bobby, a valentine to the politics and morals of Robert F. Kennedy, which drew moderate critical attention, and became a minor box office success. The film's cast included Laurence Fishburne, Anthony Hopkins, Ashton Kutcher, William H. Macy, Demi Moore, and Sharon Stone, but most of her scenes were with Shia LaBeouf and Brian Geraghty. She and her co-stars were nominated for the Screen Actors Guild Award for Best Cast in a Motion Picture but won the Hollywood Film Festival Award for Best Ensemble Cast.

In 2007, Winstead appeared in a pair of high-profile event films. Quentin Tarantino cast her as a well-intentioned but vapid and naïve actress in his high-speed segment of Grindhouse called Death Proof, his half of a double-billed feature. The film failed to produce ticket sales, but drew critical acclaim. Death Proof is the second film to feature Winstead with Kurt Russell (the first being Sky High). Winstead appeared in most of the films marketing campaigns, possibly due to her clothes which resemble Uma Thurman's character in Kill Bill, Tarantino's earlier film. The same summer, hot off the heels of its release, Winstead received another shot at action as John McClane's estranged daughter Lucy in Live Free or Die Hard. The film earned over $130 million domestically, making it the highest grossing film that features Winstead.

In 2008, Winstead screen-tested for the role of Wonder Woman in the film adaption of Justice League. She starred in a lead role in Make It Happen, a dance film. The film went straight to DVD in the US, and gained a small collection in the UK, which eventually led to its financial failure. Nevertheless, the film proved a delight for Winstead to shoot, as she had always dreamed about becoming a dancer. It was also announced on May 16, 2008, that Winstead would co-star opposite Michael Cera in the comic-book adaptation Scott Pilgrim vs. The World, under the direction of Edgar Wright. Filming began in early March 2009 and wrapped on August 28, 2009. Also co-starring were Chris Evans and Brandon Routh. The film had a U.S. release on August 13, 2010. On February 2010, Winstead landed the lead role in the prequel to The Thing, which is directed by Matthijs van Heijningen Jr. and tentatively set for an April 29, 2011 release.

Winstead has expressed interest in returning as Lucy McClane for the fifth installment of the Die Hard film series, although her involvement in the project is yet to be confirmed. She was also mentioned in news regarding the prequel to The Ring (tentatively titled The Ring 3D), though further information is yet unknown.

In August 2010, shortly before the release of Scott Pilgrim vs. the World, news emerge regarding Winstead's potential upcoming project, a romcom penned by Elan Mastai, The F Word. Casey Affleck is set to star, while Winstead is up for the female lead, testing against Rebecca Hall, Rose Byrne and Deborah Ann Woll. Later in the same month, Winstead was revealed to be "in the running" to be casted as the female lead in the Spider-Man reboot, but on August 19th, was reportedly "dropped from the running".

Interviewed in 2006, Winstead said she was in a long-term relationship with Riley Stearns, an aspiring director from Austin, Texas. In 2008, they worked together in Stop/Eject – a short film he was making with Winstead's Final Destination 3 co-star Ryan Merriman, which is as of yet still in post-production. The project was shot on the weekends during the 2008 writers' strike. Winstead elaborates, "The whole short is 25 minutes long. We're currently working on post sound and music and we hope to show it at festivals."

On July 22, 2010, Winstead announced her engagement to Stearns during an interview with Spin.com. The wedding is to take place in October 2010 in Austin, Texas.

Winstead had stated that at one point, Final Destination 3 co-star Amanda Crew "stayed with [her] for a while". She has also called Lacey Chabert her "confidant" and in the same interview, says she is good friends with Death Proof co-stars Rosario Dawson and Sydney Tamiia Poitier. "I'm not a really "cliquish" type of person," she says of herself. "There's usually one person that I gravitate to, who I feel I relate to the most, and kind of stick to throughout the whole thing." While filming Scott Pilgrim vs. the World, Winstead made good friends with co-star Anna Kendrick. “The two of us, we were just sitting up there watching the first fight [scene] in the balcony together for a week and a half, and we were always talking about gossip, film news and just gabbing about everything!”