Khalifa released his first mixtape, Prince of the City: Welcome to Pistolvania, in 2005. The mixtape led to his first full length album entitled Show and Prove in 2006. Khalifa was declared an "artist to watch" that year in Rolling Stone magazine.

In 2007, Khalifa signed to Warner Bros. Records and released two mixtapes through Rostrum Records: Grow Season, hosted by DJ Green Lantern and released on July 4, 2007, and Prince of the City 2, released on November 20, 2007. His debut Warner Bros. single "Say Yeah" reached number 25 on the Billboard Rhythmic Top 40 music chart and number 20 on Billboard's Hot Rap Tracks. The song samples "Better Off Alone" by Alice Deejay. Khalifa's vocals from "Say Yeah" appear near the end of Pittsburgh mash up producer Girl Talk's 2008 album, Feed the Animals, over music from Underworld's "Born Slippy", Usher's "Love in This Club", and the Cure's "In Between Days". Khalifa appeared with The Game, David Banner and Play-n-Skillz at U92's Summer Jam at the USANA Amphitheatre in West Valley City, Utah on August 2, 2008. Khalifa released the mixtapes Star Power in September 2008, and Flight School in April 2009 on Rostrum Records.

Khalifa parted ways with Warner Bros. Records in July 2009 after numerous delays in releasing his planned debut album for the label, First Flight. Khalifa stated to the Pittsburgh Post-Gazette that, "I learned a lot during my time there and matured as an artist during the process. I'm happy to be moving on with all of my material and having the chance to be in control of my next moves". Khalifa appeared with Girl Talk, Modey Lemon, Donora, Grand Buffet, and Don Caballero at the Amphitheatre at Station Square in Pittsburgh on July 31, 2009, where he announced that his relationship with Warner Bros. was over.

Continuing his association with Rostrum Records, Khalifa released the single "Teach U to Fly", and the mixtape How Fly, a collaboration with New Orleans rapper Curren$y, on August 9, 2009. Khalifa introduced a more melodic style on the mixtape, alternating between singing and rapping. He opened for Wu-Tang Clan member U-God at the 2009 CMJ Music Marathon in New York City. Khalifa released the mixtape Burn After Rolling on November 2, 2009, where he raps over familiar beats from other artists, including the songs "If I Were A Boy" and "Diva" by Beyoncé, "Walking on a Dream" by Empire of the Sun, "Luchini AKA This Is It" by Camp Lo, and "Best I Ever Had" by Drake.

Khalifa released his second album, Deal or No Deal, on November 24, 2009.
Photograph of Wiz Khalifa
Wiz Khalifa performing at Columbia University in New York City in April 2010.

Khalifa performed at Emo's in Austin, Texas in March 2010 as part of the 2010 South by Southwest Music Festival. He appeared on the cover of XXL magazine that same month, for the magazine's annual list of Top 10 Freshman, which included J. Cole, Pill, Freddie Gibbs, and Fashawn. He toured with rapper Yelawolf on a 20-date tour, the Deal Or No Deal Tour.[14] Khalifa released the free mixtape Kush and Orange Juice for download on April 14, 2010. Due to Khalifa's devoted grassroots fan base, the mixtape became the No. 1 trending topic on Twitter with the hash tag #kushandorangejuice, and "Kush and Orange Juice download” ranked No. 1 on Google’s hot search trends.

Citing music industry insiders, New York magazine wrote that Khalifa signed with Atlantic Records in April 2010, although the rapper didn't confirm it. He stated to AllHipHop in June 2010 that he was working on a new album, but was weighing his options and hadn't yet decided on a label to distribute it. Khalifa guested on the mixtape Grey Goose, Head Phones, and Thirsty Women by St. Louis rapper M.C.He will perform at the 2010 Rock the Bells festival, along with hip hop veterans Wu-Tang Clan,Snoop Dogg, Lauryn Hill, A Tribe Called Quest, Rakim, KRS-One, Jedi Mind Tricks and Slick Rick.