In the early 2000s, LaBeouf became known among young audiences after playing Louis Stevens on the Disney Channel weekly program Even Stevens, a role that later earned him a Daytime Emmy Award. He has said that “[he] grew up on that show” and being cast was the “best thing” that happened to him. In the next several years, he appeared in the film Holes (2003), which received praise. In 2005, he co-starred in Constantine, playing the role of Chas Kramer, with Keanu Reeves in the starring role. The same year he provided the voice of Asbel in the Disney-produced English dub of Nausicaä of the Valley of the Wind. LaBeouf made his directorial debut with the short film Let’s Love Hate with Lorenzo Eduardo. He has played real-life people, including golfer Francis Ouimet and the younger version of Dito Montiel in A Guide to Recognizing Your Saints (2006).

LaBeouf starred in Disturbia, a thriller released on April 13, 2007, as a teenager under house arrest who suspects that his neighbor is a serial killer, which he considered a “character-driven” role. He received positive reviews for the role, with The Buffalo News saying, he “is able to simultaneously pull off [the character’s] anger, remorse and intelligence”. He hosted Saturday Night Live on April 14, 2007, and returned the following season to host the episode that aired on May 10, 2008. He next played Sam Witwicky, who becomes involved in the Autobot-Decepticon war on Earth, in Transformers.

LaBeouf contributed an essay to the book I Am Jewish, by Judea Pearl, in which he stated that he has a “personal relationship with God that happens to work within the confines of Judaism”. He has described himself as Jewish, but declared in 2007 that religion had “never made sense” to him. However, he said in an interview in Interview magazine in October 2014 that he had become “a Christian man”. He suffers from post-traumatic stress disorder.

LaBeouf reprised the role of Sam Witwicky in the 2009 sequel to Transformers, Transformers: Revenge of the Fallen. Filming for the movie began in May 2008 and ended in late 2008. Due to LaBeouf’s injury from his car accident, director Michael Bay and screenwriter Roberto Orci had to rewrite the script to protect his hand throughout filming. LaBeouf said production was only delayed two days after his accident because Bay made up for it by filming second unit scenes, and LaBeouf recovered a few weeks earlier than expected, allowing him to return to the set. Near the end of filming, LaBeouf injured his eye when he hit a prop; the injury required seven stitches. He resumed filming two hours later. While the movie grossed $800 million, it received mostly negative reviews by critics, with LaBeouf sharing a nomination for the “Worst Screen Couple of 2009” Razzie Award with “either Megan Fox or any Transformer.”

He appeared in the Oliver Stone-directed film Wall Street: Money Never Sleeps (2010), the sequel to Wall Street (1987). In this, LaBeouf played an ambitious Wall Street trader. The Hollywood Reporter named LaBeouf as one of the young male actors who are “pushing – or being pushed” into taking over Hollywood as the new “A-List”. LaBeouf completed the 2010 Los Angeles Marathon on March 21, 2010 with a time of 4 hours, 35 minutes and 31 seconds.

He reprised his role in the third live-action Transformers film, Transformers: Dark of the Moon, which was released on June 28, 2011. He did not return for the fourth film in the series, Transformers: Age of Extinction, and Mark Wahlberg was cast as a new lead character. In 2012, Rob Cantor of Tally Hall produced a song describing LaBeouf as a murderous cannibal. In 2014, Cantor produced a music video based on this song. Despite the title and lyrics, the intent was humorous and non-serious, and LaBeouf appeared at the end of the video, applauding.

LaBeouf has created three short graphic novels Stale N Mate, Cyclical, and Let’s Fucking Party, and a webcomic series, Cheek Up’s through the publishing company, The Campaign Book. In April 2012, he promoted them at Chicago Comic & Entertainment Expo. In the same year, LaBeouf played a bootlegger in John Hillcoat’s crime drama Lawless. In June 2012, Icelandic band Sigur Rós released a music video for the song “Fjögur Píanó”. It depicts “a man and woman locked in a never-ending cycle of addiction and desire”, in which LaBeouf stars and appears nude.

He met his co-star and later girlfriend, English actress Mia Goth, while filming Nymphomaniac in 2012. On October 10, 2016, LaBeouf and Goth appeared to have gotten married in a Las Vegas ceremony officiated by an Elvis impersonator. Two days later, a local official said that the pair was not legally married, but instead a commitment ceremony was performed. Later that month, LaBeouf confirmed their nuptials on The Ellen DeGeneres Show. In September 2018, it was announced the couple had separated and filed for divorce.

In February 2013, he pulled out of what would have been his Broadway debut, in Lyle Kessler’s play Orphans, citing “creative differences” with co-star Alec Baldwin, although The New York Times and Baldwin himself maintain LaBeouf was fired. A month later, a film in which he starred alongside Robert Redford entitled The Company You Keep was released. He next portrayed Jerôme Morris in the Lars von Trier-directed erotic art film Nymphomaniac, which premiered in December 2013. LaBeouf co-starred with Brad Pitt and Logan Lerman in David Ayer’s World War II-set film, Fury, which was released in October 2014. Peter Travers of Rolling Stone called LaBeouf’s performance “outstanding”, whilst New York Daily News’s Joe Neumaier commented that he “finally finds a role he can disappear into, without his image getting in the way.” Calvin Wilson of St. Louis Post-Dispatch called LaBeouf’s performance one of his best.

On December 17, 2013, LaBeouf released his short film Howard Cantour.com to the Internet; shortly thereafter, several bloggers noted its close similarity to Justin M. Damiano, a 2007 comic by Ghost World creator Dan Clowes. Wired journalist Graeme McMillan noted at least three similarities in their article, one of which was that the opening monologue for the short and the comic were identical. LaBeouf would later remove the film and claim that he did not intend to copy Clowes but was instead “inspired” by him and “got lost in the creative process.” He followed this up with several apologies via Twitter writing, “In my excitement and naiveté as an amateur filmmaker, I got lost in the creative process and neglected to follow proper accreditation”, and “I deeply regret the manner in which these events have unfolded and want @danielclowes to know that I have a great respect for his work”. Clowes responded by saying “The first I ever heard of the film was this morning when someone sent me a link. I’ve never spoken to or met Mr. LaBeouf … I actually can’t imagine what was going through his mind.” LaBeouf was criticized over his apology, with some sites such as The A.V. Club noting that the apology itself appeared to have been lifted from a 2010 post on Yahoo! Answers.

In early 2014, LaBeouf began collaborating with British artist and author of The Metamodernist Manifesto, Luke Turner, and Finnish artist Nastja Säde Rönkkö, embarking on a series of actions described by Dazed as “a multi-platform meditation on celebrity and vulnerability”. Since then, LaBeouf, Rönkkö & Turner have engaged in numerous high-profile performance art projects, including #IAMSORRY (2014), #ALLMYMOVIES (2015), #TOUCHMYSOUL (2015), #TAKEMEANYWHERE (2016), and HEWILLNOTDIVIDE.US (2017–present).

On February 9, 2014, the artists caused controversy at the Berlin Film Festival when LaBeouf arrived at the red carpet wearing a brown paper bag over his head with the words “I AM NOT FAMOUS ANYMORE” written on it. In a conversation conducted as part of the trio’s #INTERVIEW piece in November 2014, LaBeouf said that he was “heartbroken” and “genuinely remorseful and full of shame and guilt” at the start of their subsequent #IAMSORRY performance, in which he occupied a Los Angeles gallery for six days wearing the paper bag and silently crying in front of visitors, but that “in the end I felt cared for however it came—it was beautiful, it blew me away.” He revealed, however, that one woman had proceeded to sexually assault him during the February performance, while Rönkkö and Turner later clarified that they had prevented the assault by intervening as soon as they were aware of the incident starting to occur.

In January 2014, LaBeouf spoke about the plagiarism accusations with Bleeding Cool writer Rich Johnston, where he stated that he saw copyright laws as too restrictive and that they did not allow for ideas to flow freely. LaBeouf later tweeted a description of his next project, Daniel Boring (a reference to David Boring, another comic created by Clowes). The description of the project was also taken word-for-word from a description by Clowes of his comic. Clowes’ attorney, Michael Kump, has since sent a cease-and-desist letter to LaBeouf’s attorney, which LaBeouf posted on Twitter.

On June 26, 2014, LaBeouf was arrested at New York City’s Studio 54 theater and subsequently charged with disorderly conduct, harassment, and criminal trespass. He was said to have been “acting disorderly, yelling and being loud”. Following the incident, LaBeouf voluntarily sought outpatient treatment for alcoholism. He pleaded guilty to disorderly conduct, while the trespassing and harassment charges were dropped.

In 2015, LaBeouf starred in Sia’s music video for “Elastic Heart” along with Maddie Ziegler. He also starred in the war-thriller film Man Down directed by Dito Montiel alongside Gary Oldman and Kate Mara. In 2016, LaBeouf starred in American Honey, directed by Andrea Arnold, playing the male lead role, Jake. In Variety, Guy Lodge wrote that “despite the apparent stunt casting of LaBeouf”, he “easily delivers his best performance here, bleeding the eccentricities of his own celebrity persona into the character to fascinating, oddly moving effect”. In 2017, he portrayed tennis player John McEnroe in the Swedish sports drama film Borg vs McEnroe.

In 2015, LaBeouf appeared in #INTRODUCTIONS, a half-hour video made by LaBeouf, Rönkkö & Turner in collaboration with Central Saint Martins Fine Art students, comprising a series of short monologues performed by LaBeouf in front of a green screen. One segment in the form of an exaggerated motivational speech, dubbed “Just Do It” after the Nike slogan, became an Internet meme after going viral within days of being released, spawning numerous remixes and parodies, and becoming the most searched for GIF of 2015 according to Google.

In 2015, LaBeouf endorsed Jeremy Corbyn’s campaign in the Labour Party leadership election. He told the Evening Standard: “I like Jeremy Corbyn. I like him in every way. British politics just got very exciting.”

On July 8, 2017, LaBeouf was arrested in downtown Savannah, Georgia at around 4 a.m. for public intoxication, disorderly conduct, and obstruction. After pleading no contest to the charge of disorderly conduct in October 2017, LaBeouf was found guilty of obstruction but was found not guilty of public intoxication. He was sentenced to probation for one year, including time served, and ordered to pay a $1,000 fine as well as seek therapy to manage his anger and substance use issues.

In 2019, he starred in the comedy-drama film The Peanut Butter Falcon, which premiered in March, and was released in August. In the same year, LaBeouf wrote and starred in Honey Boy, portraying a character based on his father. He penned the screenplay while in rehab, based upon his life as an actor. Both The Peanut Butter Falcon and Honey Boy garnered acclaim from critics. The following year, LaBeouf starred in The Tax Collector, directed by David Ayer. In September 2020, he participated in a virtual reading of the comedy-drama film Fast Times at Ridgemont High.

In September 2020, LaBeouf was charged with misdemeanor battery and petty theft for his involvement in an altercation with a man in June.