In 2004, the Roots released The Tipping Point, which contained a more mainstream sound, allegedly due to demands from Interscope Records. The album sold 400,000 copies. In 2004, Questlove appeared in Jay-Z's Fade to Black. In addition to appearing in the documentary portion of the film, Questlove was the drummer/musical director for all portions of the show with a live band. In 2005, Questlove appeared along with performers including Madonna, Iggy Pop, Bootsy Collins, and Little Richard in a television commercial for the Motorola ROKR phone.
In 2006, Questlove appeared in the film Dave Chappelle's Block Party, as well as a couple of skits on Chappelle's Show. These included the Tupac "The Lost Episodes" skit, and one featuring John Mayer, wherein Questlove performs in a barber shop, inducing the occupants to dance and rap. With the exception of the Fugees and Jill Scott, Questlove served as the drummer at the 2004 Brooklyn street concert and was the musical director for the entire show. Questlove was given an Esky for Best Scribe in Esquire magazine's 2006 Esky Music Awards in the April issue. In 2006, Questlove was one of a handful of musicians hand-picked by Steve Van Zandt to back Hank Williams Jr. on a new version of "All My Rowdy Friends Are Coming Over Tonight" for the season premiere (and formal ESPN debut) of Monday Night Football. Along with his fellow Motorola ROKR commercial co-stars, Bootsy Collins and Little Richard, Questlove's bandmates included Rick Nielsen (Cheap Trick), Joe Perry (Aerosmith), Charlie Daniels, and Bernie Worrell. In the same year, he appeared in the studio album Fly of the Italian singer Zucchero Fornaciari.
In 2007, Questlove co-produced with VH1's The Score winning producer Antonio "DJ Satisfaction" Gonzalez, from the Maniac Agenda, the theme to VH1's Hip Hop Honors 2007. Questlove joined Ben Harper and John Paul Jones for the Bonnaroo SuperJam on June 16, 2007, to play a 97-minute set.
On March 2, 2009, Questlove and the Roots began their run as house band for Late Night with Jimmy Fallon. He continues to perform with the Roots on The Tonight Show Starring Jimmy Fallon, continuing his duties from Late Night with Jimmy Fallon. He occasionally performed solos titled 're-mixing the clips', where he drew on his production and DJ abilities to dub video clips, cue audio samples in rhythm, and play drum breaks simultaneously.
In late 2009, while serving as an associate producer of the hit Broadway play Fela!, Questlove recruited Jay-Z to come on board as a producer. It was reported that Will Smith and Jada Pinkett Smith had also signed on as producers.
In January 2010, he was writing material with British singer Duffy for her second album. He has been featured in a commercial for Microsoft's short-lived mobile phone, the Kin. In 2010, he made a cameo in the music video of Duck Sauce's song "Barbra Streisand", and with the Roots released the album Dilla Joints with renditions of producer J Dilla's music. He contributed drums to the song "You Got a Lot to Learn", which was recorded for the self-titled third studio album by Evanescence, but did not appear on the final release.
Questlove was planning to collaborate with Amy Winehouse before her death in July 2011. He said "We're Skype buddies, and she wants to do a project with Mos and me. Soon as she gets her visa thing together, that's gonna happen." Rolling Stone named Questlove number 2 in the 50 Top Tweeters in Music. In June 2011, Questlove played drums alongside the Roots bassist Owen Biddle for Karmin's cover of Nicki Minaj's "Super Bass." Questlove placed 8th in the Rolling Stone Readers Pick for Best Drummers of all Time.
In September 2016, Questlove launched a weekly radio show on Pandora, Questlove Supreme. Notable guests have included Solange, Chris Rock, Maya Rudolph, and Pete Rock, among others. In 2019, Questlove Supreme moved from Pandora to iHeart Radio, where it still continues to this day. The podcast has won "Best Music Podcast" at the 2023 iHeart Podcast Awards, "Interview Of The Year" and "Podcast Of The Year" at Adweek's 2023 Audio Awards, Best Lifestyle Podcast" at the 2022 Webby Awards, along with other wins and nominations.
Alec Baldwin interviewed Questlove for the January 3, 2017, episode of Baldwin's WNYC Studios podcast Here's the Thing, where he joked about being "obsessed" with his Wikipedia profile. During the interview, he also discussed his musical and cultural interests, how the Roots started a "movement" with three 15-passenger vans and the impact of the loss of musical icons in 2016.
In 2019, Questlove partnered with Black Thought of The Roots to executive produce the documentary series Hip-Hop: The Songs That Shook America under their production company, Two One Five Entertainment. The series aired on AMC. In 2020, the pair announced a first-look deal with Universal Television to develop scripted and non-scripted programming.
He also served as the musical director and in-house DJ of the 2021 Academy Awards ceremony, having previously served as the in-house DJ for the 2020 ceremony. The music for the 2021 ceremony was largely remixed from compositions created by his band The Roots, with no in-house orchestra present.
In 2021, Questlove made his directorial debut with Summer of Soul (...Or, When the Revolution Could Not Be Televised), a film about the 1969 Harlem Cultural Festival, which featured performances by Stevie Wonder, Sly and The Family Stone, Nina Simone, Mahalia Jackson, Mavis Staples, B. B. King, and many other top soul, jazz, gospel, and Latin artists of the era. Summer of Soul won both the US Grand Jury Prize and the Audience Award for documentary at the 2021 Sundance Film Festival. Disney-owned Searchlight Pictures acquired the film for distribution, setting a new Sundance Film Festival record for documentary film acquisition price. The film received acclaim from critics, with particular praise given to the restoration of the footage used. The film won numerous awards, including Best Documentary Feature at the 6th Critics' Choice Documentary Awards, where it won in all six categories in which it was nominated, Best Documentary at the 75th British Academy Film Awards, Best Documentary Feature at the 94th Academy Awards, and Best Music Film at the 64th Annual Grammy Awards.
In September 2022, it was announced that Questlove would executive produce a feature documentary about J Dilla titled Dilla Time, adapted from the Dan Charnas biography of the same name. Joseph Patel, who also produced Summer of Soul, and Darby Wheeler are slated to co-direct. In the same year, Questlove executive produced Descendant, a feature documentary on the historic discovery of The Clotilda—the last known slave ship to arrive in America illegally transporting enslaved Africans. The documentary, which made its world premiere at Sundance in 2022, was acquired by Netflix and Higher Ground, President Barack Obama and Michelle Obama's production company. The film earned several award nominations at the 2022 Critics Choice Documentary Awards, 2023 NAACP Image Awards and was also named one of the "Top 5 Documentaries" of 2022 by the National Board of Review.
In March 2023, it was announced that Questlove would direct a live-action/hybrid reimagining of the Walt Disney Productions animated film The Aristocats as his feature-film directorial debut, as well as executive-producing and overseeing the music. Will Gluck and Keith Bunin were attached to write the script, and Tariq Trotter, Shawn Gee and Zarah Zohlman were attached to executive produce on behalf of Two One Five Entertainment. Gluck and his production company Olive Bridge Entertainment were slated to produce. In August 2025, however, Questlove revealed that Disney was no longer moving forward with the film.
Questlove and Black Thought, under their Two One Five banner, executively produced Rise Up, Sing Out, a collection of animated musical shorts for Disney Junior, which earned a nomination for "Outstanding Short Form Series" for the 2023 NAACP Image Awards. Questlove's web series, Quest for Craft, produced by Two One Five and launched in partnership with the single malt whiskey brand, The Balvenie, took home a Webby Award in 2023. In 2023, Questlove also executive produced Sam Pollard's The League, a documentary centered on Negro league baseball. Questlove executive produced the A&E James Brown docuseries Say It Loud, which aired in 2024.
Questlove directed Sly Lives!, a documentary film about funk musician Sly Stone, which was released on Hulu in February 2025.