On 1 July 2010, he moved back to Genoa. After a link with Inter Milan in February 2010, the clubs agreed a deal in June 2010 which involved the transfer of young striker Mattia Destro. The transfer became official on 20 July 2010, which Inter signed half of the registration rights of Ranocchia for €6.5 million and sent Destro on loan to Genoa with option to sign him in co-ownership deal (who later purchased outright for €4.5 million). Ranocchia also loaned back to Genoa for a season.
On 27 December 2010, Inter bought the remaining 50% registration rights of Ranocchia from Genoa for €12.5 million, valuing him at €19 million in total, which was later confirmed by Genoa chairman Enrico Preziosi who expressed his delight at doing business with Inter. The chairman of Inter, Massimo Moratti, spoke on the transfer to Sky Italia and said: "Finally an Italian. We had kept an eye on him from before. It is our project to go ahead with young players." On 9 January 2011, Ranocchia made his Inter debut in a 2–1 win over Catania in Serie A. He made his Champions League debut against Bayern Munich in the first leg of the round of 16; Inter eventually progressed to the quarter-finals where they were eliminated by eventual semi-finalists Schalke 04. Ranocchia completed his first season with Inter by attaining a second-place finish in Serie A, also winning the 2010–11 Coppa Italia; the following season, however, Inter lost out to Serie A Champions and cross-city rivals Milan in the 2011 Supercoppa Italiana Final.
He made his debut with the Italy senior team on 17 November 2010, in a friendly match against Romania, which ended in a 1–1 draw.