Lilly was discovered on the streets of Kelowna, British Columbia, by Ford modeling agency. Although she initially decided to pass on a modeling career, she went ahead and signed with Ford anyway, to help pay for her University of British Columbia tuition and expenses. Despite being signed to Ford Models, she was never actually a fashion model, working instead with their acting branch. She was previously featured in several provocative television commercials for LiveLinks Chatline, a service billed as the "best place to meet local singles for dating, friendship, or phone chat." Her image is still used to promote the service. She also appeared on G4's Judgment Day. She appeared uncredited in the 2003 film Freddy vs. Jason as a high-school girl leaning against a locker, and in several episodes of Smallville as an extra. She also had a guest appearance on the ABC supernatural horror series Kingdom Hospital (2004). Lilly's first speaking role was on Lost. She also appeared in the 2003 teenager film The Lizzie McGuire Movie as an (uncredited) Italian police officer.

When Lilly was cast as Kate in Lost, her main concern was acquiring a work visa to enter the United States. With production literally days away and no news about the visa, casting directors were forced to grudgingly begin re-casting the role of Kate. After nearly 20 auditions, Lilly's work visa was approved/cleared but she arrived on set a day late. Her salary in 2004 for Lost was $80,000 per episode. On the heels of her role in Lost, she was voted one of the Breakout Stars of 2004 by Entertainment Weekly. Although Lilly placed 13th in the FHM "100 Sexiest Women in the World" of 2006 and initially placed 2nd on Maxim's "Hot 100" list of 2005, she slipped to 67th in Maxim's 2006 list. On December 14, 2006, Lilly was nominated for a Golden Globe for Best Lead Actress-Drama. Action figures of Lilly's Lost character were released during the holiday season of 2006. Lilly has recently announced that, once she has finished filming Lost, she plans to stop acting and pursue a career as a humanitarian worker; however she has not ruled out returning to TV at some point in the future.

Lilly was once married to Canadian hockey player Murray Hone, and is engaged to her former Lost co-star Dominic Monaghan. Her Lost castmates nicknamed her "Monkey" because of her ability to climb trees with ease, a skill which has been incorporated into her character. Her fellow Lost actor Josh Holloway also calls her "Freckles", sharing the nickname his on-screen character Sawyer gave her. She is also known on set for her tomboyishness, Christian faith, and her "potty mouth". Lilly has stated that she "live in a bubble", specifying that she is not familiar with popular culture and does not watch television or own a TV set. She has also said that she would not appear in a nude scene or perform in sexual scenes that she would consider "gratuitous".

On the May 9, 2007, Episode of Jimmy Kimmel Live, Evangeline Lilly described her deep need to leave her home town after her high school graduation. She did much travelling at this point in her life, moving from town to town approximately every six months. She stated that in each town she took on a persona; for example, she would decide in one town to take on the role of a "nerdy bookworm" and in another, a ditzy "cheerleader" type. She has jokingly stated that, as such, she would frequently date different men. Lilly has also used her celebrity status to help promote Just Yell Fire, a video aimed at teaching teenage girls how to defend themselves against rapists. During the summer break between the first and second seasons of Lost, Lilly spent time visiting the poor in Rwanda. On December 20, 2006, Lilly's house in Kailua, Hawaii, was completely destroyed by fire while she was on the Lost set with one of her two roommates, both of whom work as her stand-ins on the show. The second roommate was off-island at the time of the blaze, which occurred on the final day of shooting before the show’s holiday break. The cause of the fire was an electrical problem.

• "Lost" .... Kate Austen (93 episodes, 2004-2009)
       - He's Our You (2009) TV episode .... Kate Austen
       - Namaste (2009) TV episode .... Kate Austen
       - LeFleur (2009) TV episode .... Kate Austen
       - The Life and Death of Jeremy Bentham (2009) TV episode .... Kate Austen
       - 316 (2009) TV episode .... Kate Austen
        (88 more)
• Afterwards (2008) .... Claire
  ... aka Et après (France)
• The Hurt Locker (2008) .... Connie James
• The Long Weekend (2005) .... Simone
  ... aka Long Week-End, Un (Canada: French title)
• "Kingdom Hospital" .... Benton's Girlfriend (1 episode, 2004)
  ... aka Stephen King's Kingdom Hospital (USA: complete title)
       - Heartless (2004) TV episode (uncredited) .... Benton's Girlfriend
• "Tru Calling" .... Party Guest (1 episode, 2003)
       - Morning After (2003) TV episode (uncredited) .... Party Guest
• Freddy vs. Jason (2003) (uncredited) .... School Student - Next to Locker
  ... aka Freddy contre Jason (Canada: French title)
  ... aka FvJ (USA: informal short title)
• Stealing Sinatra (2003) .... Model in commercial
• "Smallville" .... Wade's Girlfriend (1 episode, 2002)
  ... aka Smallville Beginnings (USA: rerun title)
  ... aka Smallville: Superman the Early Years (UK: promotional title)
       - Kinetic (2002) TV episode (uncredited) .... Wade's Girlfriend
• "Judgment Day" (2002) TV series .... JD Girl (unknown episodes)