Gasperini first joined Genoa in 2006, leading the club to promotion to Serie A in his first season in charge, before going on to guide them a fifth-place finish in the 2008-09 campaign.
The 55-year-old was sacked in November 2010, but will now return to the Stadio Luigi Ferraris as Genoa attempt to recover from a poor start that has seen them win just one of their first six top-flight games.
Genoa slipped to a 2-0 loss at the hands of Napoli on Saturday, a result that signalled the end of Liverani's reign - which began in June as he was promoted from the position of youth team coach - after just three months in charge.
Gasperini, who has also enjoyed managerial spells with Inter and Palermo, takes over on a three-year deal.
A statement on the club's official website read: "Genoa CFC announces that it has entrusted the technical management of the first team to Gian Piero Gasperini. The agreement is reached on a triennial basis.
"The club would like to thank Fabio Liverani for his work and commitment in recent months."
Genoa narrowly avoided relegation last season, finishing in 17th place at the end of a disappointing season, which led to the sacking of Davide Ballardini.
Their form has not improved under Liverani though, with their only win this term coming with a 3-0 success at city rivals Sampdoria earlier this month.
Gasperini's first game comes next Sunday when Genoa travel to fellow strugglers Catania.
