In 2005, Pettyfer made his professional acting début in the British television production of Tom Brown’s Schooldays, playing the lead character, Tom Brown; he received positive reviews for the role. In June 2005, he was cast in his most prominent role so far, that of teenage MI6 spy Alex Rider in the film Stormbreaker, based on the novel by Anthony Horowitz. He was one of 500 who auditioned for the role. Pettyfer chose to appear in the film over a role in the film Eragon, noting that he preferred Stormbreaker because it would be filmed in Britain, in the Isle of Man, while Eragon would film in Hungary; Pettyfer has a fear of flying, and he liked the looks of the cast for Stormbreaker. Stormbreaker was released on 21 July 2006 in the United Kingdom, on 6 October 2006 in the United States and on 21 September 2006 in Australia.

One review of Pettyfer’s performance described him as playing the role with an “earnest intensity”, although another noted that he “isn’t quite at ease as an actor”. Media reports specified that the film was expected to make Pettyfer a “teen idol”. In September 2006, it was reported that Pettyfer would not reprise the role if there was another Alex Rider film because he had become too mature for the role.

He next appeared in Wild Child, a film set in California, Kent and Yorkshire part of which took place at Cobham Hall Girls’ School in Kent. He played schoolboy Freddie Kingsley and he co-starred with Emma Roberts. In 2009, he played the callous ringleader of a group of cool but cruel teenagers who are picked off one by one by the ghost of one of their former victims, in the horror-comedy, Tormented.

He starred in the film Beastly, based on the novel by Alex Flinn, alongside Mary-Kate Olsen, Vanessa Hudgens and Neil Patrick Harris. He finished filming on 13 August 2009, and the film was released on 4 March 2011. Pettyfer portrayed the main character in I Am Number Four, released in February 2011. The film co-starred Timothy Olyphant, Dianna Agron and Teresa Palmer, and was directed by D.J. Caruso, produced by Michael Bay and executive produced by Steven Spielberg.

In June 2009, Pettyfer was voted number 35 on British women’s magazine Company’s list of the top 50 most eligible bachelors. In August 2009, the British magazine Glamour ranked him number 21 on their list of the sexiest men on the planet.

In a 2011 interview, he stated “I felt like the industry was just a factory. You hear a lot of people say they want to make art in this industry, but so few people actually fucking do it. I was disillusioned by Hollywood at the time, but now I’ve come to accept that’s just the way things are: it’s called show business, not show art.”

He was offered the part of Jace Wayland in the upcoming portrayal of Cassandra Clare’s best selling book, City of Bones. Jamie Campbell Bower was later cast as Jace Wayland. Pettyfer had also been offered a part in an upcoming film adaption of Joseph Delaney’s The Wardstone Chronicles, but he declined the role. He was in line to star in The Paperboy, based on the Pete Dexter novel of the same name, but was dropped for the role (filled by Zac Efron). In 2012 he played Adam, a 19-year-old who enters the world of male stripping in Magic Mike.

Pettyfer was briefly engaged to actress Riley Keough in 2012. They met while filming Magic Mike.

In 2013, Pettyfer had a small role as Thomas Westfall in The Butler. In 2014, he starred in the romantic drama Endless Love alongside actress Gabriella Wilde, where they play love interests. In 2016, Pettyfer played the role of Jerry Schilling in the biography film Elvis & Nixon alongside Kevin Spacey and Michael Shannon. In 2017, he starred as Nick in the indie thriller The Strange Ones directed by Christopher Radcliff and Lauren Wolkstein. Pettyfer and his producing partner Craig Robinson launched Upturn Productions in 2015 with the intent of securing literary works that could be made into film or television. In 2017, Back Roads, based on the book of the same name by Tawni O’Dell, was their first independent film produced under the Upturn banner. Pettyfer made it his directorial debut and also played the lead role of Harley Altmyer.

In 2018, Pettyfer starred as Stephen Underwood, a journalist who uncovers the horrific murder of 22,000 Poles under Stalin’s instructions, in the post–World War II thriller The Last Witness. In the same year, it was announced that Pettyfer had been cast in the main role of Brody on the Netflix science fiction miniseries The I-Land. The miniseries was released on 12 September 2019.

On 24 December 2019, he became engaged to German model Toni Garrn after ten months of dating. They were married in Hamburg, Germany, in October 2020.