The 43-year-old Lopez played for the club for 12 seasons from 1998 to 2010, and previously coached the Sardinian outfit from 2013 to 2014, with a spell also in charge of the youth teams.
Lopez — who also briefly coached Palermo in Serie A last season and Bologna when they were in the second division — signed a contract until June 2019, the club said.
Cagliari are currently 14th in Serie A after four straight defeats, most recently losing 3-2 at home against Genoa.
Rastelli, 48, took over in the 2015-2016 season, guiding Cagliari into the Italian top flight after winning Serie B in 2016.
Last season the club finished 11th but this term are struggling with just two wins in eight games, against relegation rivals Crotone and SPAL.
Rastelli was the first Serie A coach sacked this season with coaching assistants Nicola Legrottaglie and Dario Rossi also dismissed in the clearout.