Dobrev’s first major acting role was as Mia on the teen drama television series Degrassi: The Next Generation, a role she played for three seasons starting in 2006. She appeared in several feature films in the mid-2000s, including Fugitive Pieces and Away from Her. Dobrev also headlined a number of television films, including Sci Fi Channel’s Never Cry Werewolf, MTV’s The American Mall, and two Lifetime original movies. In 2007 she appeared in the music video of “You Got That Light” performed by Wade Allain-Marcus and David Baum.

Dobrev left Degrassi in 2009 to star in The CW’s supernatural drama series The Vampire Diaries, a television adaptation of the book series of the same name, playing the lead role of Elena Gilbert. Dobrev recurrently played a 500-year-old doppelgänger vampire named Katherine Pierce. She played the Petrova doppelgänger progenitor Amara, also known as the world’s first immortal, in season 5. She crossed over to The Vampire Diaries spinoff The Originals, as doppelgänger character Tatia, in an episode in 2014. In April 2015, Dobrev announced via Instagram that she would be leaving The Vampire Diaries after portraying Elena for six seasons. In January 2017, it was announced that Dobrev would return as Elena and Katherine in The Vampire Diaries series finale.

Dobrev had a minor role in the erotic thriller Chloe, theatrically released by Sony Pictures Classics on March 26, 2010. The film had enjoyed commercial success and became director Atom Egoyan’s biggest moneymaker ever. She also had a small role in the 2011 film The Roommate.

In April 2011, Dobrev was cast as Candace Kelmeckis in the film adaptation of The Perks of Being a Wallflower, alongside Logan Lerman, Emma Watson, and Paul Rudd. In August 2014, she starred alongside Jake Johnson and Damon Wayans Jr. in the 20th Century Fox comedy Let’s Be Cops.

Dobrev is an enthusiastic volunteer and uses her reputation to support many charitable causes, including Puma’s 2011 non-profit “Project Pink” which supports numerous breast cancer charities and “Hunger Bites” organization that is dedicated to reducing hunger in 27 districts across Pennsylvania. Dobrev is also recognized for her long term involvement with WE movement, a Canadian-based charity which empowers youth to be agents of change. Dobrev took part in a Me to We volunteer trip to Kenya to help build a school. She has hosted We Day event in Toronto back in 2011 and made an appearance on stage at WE Day California 2019. Other social and charity issues Dobrev has been involved with include communities in Schools, school supplies, Elton John AIDS Foundation and “Rape Foundation” which gives comprehensive care to rape victims and sexually abused children.

Dobrev played the role of Vicki Summers in the 2015 horror comedy film The Final Girls. In September 2015, Dobrev was cast in the film Arrivals, opposite Asa Butterfield and Maisie Williams, portraying the role of flight attendant Izzy; the film was later retitled Departures, and was scheduled to go into production in April 2017. The same year, she was cast in the romantic comedy Crash Pad, alongside Domhnall Gleeson and Christina Applegate, which began filming in Vancouver in fall 2015.

Dobrev speaks English, French and Bulgarian. While filming The Vampire Diaries, Dobrev lived in Atlanta, but moved to Los Angeles after leaving the series in 2015.

In 2017, Dobrev co-starred as weapons specialist Becky Clearidge in the action film sequel XXX: Return of Xander Cage, opposite Vin Diesel and Samuel L. Jackson; the film was released January 20. Also that year, Dobrev co-starred as Marlo in the film remake Flatliners, opposite Ellen Page.

In March 2018, Dobrev was cast in the role of Clem in the comedy Fam, a CBS television pilot that was picked up to series in May 2018. The sitcom premiered January 10, 2019. On May 10, 2019, the series was cancelled after one season. Dobrev starred as Chloe in the Roger Avary thriller Lucky Day, released 2019. In 2019, she joined the cast of the film Run This Town, which was released in March 2020. In July 2020, it was announced that Dobrev would star in and serve as executive producer for a television adaptation of the Woman 99 book series.