Jackson released his debut album, Get Rich or Die Tryin' (described by AllMusic as "probably the most hyped debut album by a rap artist in about a decade"), in February 2003. Rolling Stone noted its "dark synth grooves, buzzy keyboards and a persistently funky bounce", with Jackson complementing the production in "an unflappable, laid-back flow". It debuted at number one on the Billboard 200, selling 872,000 copies in its first four days. The lead single, "In da Club" (noted by The Source for its "blaring horns, funky organs, guitar riffs and sparse hand claps"), set a Billboard record as the most listened-to song in radio history within a week.
Interscope gave Jackson his own label, G-Unit Records, in 2003. He signed Lloyd Banks, Tony Yayo and Young Buck as members of G-Unit, and The Game was later signed in a joint venture with Dr. Dre's Aftermath Entertainment. In March 2005, Jackson's second commercial album, The Massacre, sold 1.14 million copies in its first four days (the highest in an abbreviated sales cycle) and was number one on the Billboard 200 for six weeks. He was the first solo artist with three singles in the Billboard top five in the same week with "Candy Shop", "Disco Inferno" and "How We Do". According to Rolling Stone, "50's secret weapon is his singing voice - the deceptively amateur-sounding tenor croon that he deploys on almost every chorus".
Jackson has had a highly successful business career. He is financially invested in a highly diversified variety of industries. Jackson is now involved in artist and talent management, record, television, and film production, footwear, apparel, fragrances, liquor, video games, mobile apps, book publishing, headphones and health drinks and dietary supplements. His broad business and investment portfolio contains investments in a variety of sectors including real estate, financial market investments, mining, boxing promotion, vodka, fragrances, consumer electronics and fashion. He established his own record label G-Unit Records in 2003 following his mainstream success. In November 2003, he signed a five-year deal with Reebok to distribute a G-Unit Sneakers line for his G-Unit Clothing Company. In an interview, Jackson said his businesses had a habit of doing well as he saw all of his ventures both past and present as revolving around his alter ego. Jackson has also started a book publishing imprint, G-Unit Books on January 4, 2007 at the Time Warner Building in New York. He has written a number of books including a memoir, From Pieces To Weight in 2005 where it sold 73,000 copies in hardcover and 14,000 copies in paperback; a crime novel and a book with Robert Greene titled The 50th Law, an urban take on The 48 Laws of Power. In November 2011, Jackson released 50 Cent's Playground, a young adult fiction novel about a bullied, violent boy and his gay mother.
Jackson has founded two film production companies: G-Unit Films in 2003 and Cheetah Vision in 2008. Cheetah Vision produces low budget action thrillers for foreign film markets across the world. When G-Unit Films folded, he focused on Cheetah Vision and the company obtained $200 million in funding in 2010. In 2010, Jackson revived G-Unit Films, renaming the company to G-Unit Films and Television Inc. The company has joint ventures with Will Packer's production company Will Packer Productions and Universal Television. In over 18 months, Jackson has sold projects to six different networks. Among them was Power, a STARZ drama in which he not only co-stars but also serves as co-creator and executive producer. Power debuted in June 2014 and was renewed for a second season after one episode. Power's August 2 season finale garnered the high ratings through the season, more than doubling the premiere and it generated 71% of the African-American viewership of any scripted premium series since 2006. Jackson serves as a co‐star, co-creator and executive television producer of the STARZ network drama where he signed a 2-year contract with representation coming from the Agency for the Performing Arts. Ratings have been a success for Starz. with the second-season premiere being the highest-ever season with 1.43 million people tuning in live. Jackson also serves as an executive television producer for Dream School for SundanceTV, a series that follows fifteen high school dropouts as they are taught by a series of celebrity "teachers".