Åkesson has been playing guitar since the age of 12. His early musical influences include Michael Schenker, Uli Jon Roth, Yngwie Malmsteen and George Lynch. Marcel Jacob, founder of Talisman, held auditions in 1992 to find a new guitar player after Jason Bieler left them to play with Saigon Kick; the 19-year-old Åkesson was selected for the position. He spent almost four years with Talisman and after five records decided to leave them for a heavier outfit. Åkesson, Mats Levén, John Levén, and Rickard Evensand formed a band called Eyeball who would later change their name to Southpaw. In 1998 Åkesson was appeared on two albums: Southpaw's debut album and Naïve by Clockwise. He also recorded a version of Journey's classic "Send Her My Love" with Clockwise for a tribute album that was never released.
In Åkesson he returned to record and tour with Talisman. They worked on two new studio efforts: Cats and Dogs (2003) and 7 (2006) plus a live album called Five Men Live (2005) which was released on DVD as World's Best Kept Secret. In 2004, Åkesson filled in for Tiamat guitarist Thomas Petersson on tour and was featured in the The Church of Tiamat DVD release in 2006. He also appeared on the Sabbtail album Night Church, again with Mats Levén.
On 17 May 2007 the progressive death metal band Opeth announced that Åkesson would replace departed guitarist Peter Lindgren. Åkesson's first tour with the band was the Progressive Nation Tour with Dream Theater and Between the Buried and Me. Åkesson's first album with Opeth was Watershed (2008) in which he co-wrote the song "Porcelain Heart" with Mikael Åkerfeldt. The album Heritage was released in September 2011, also with one song (the bonus track "Pyre") co-written by Åkesson.
Fredrik Åkesson had an endorsement arrangement with ESP Guitars which continued into 2007. He also had his own signature model. Since joining Opeth, Åkesson switched to PRS Guitars with Marshall JVM 410 amps and cabs. In the "Porcelain Heart" videoclip he can be seen using a PRS Mark Tremonti Signature guitar. In 2009, Fredrik has switched to Blackstar Amplification, using the Series One 200. In addition to his Blackstar amps, Fredrik also uses Fractal Audio's Axe FX effects processor. He left Blackstar in 2012, switching his endorsement to Marshall amps. In 2011, PRS guitars produced his signature model PRS.