The Pope left for the Vatican at 12.50 a.m. from an airport in Seongnam, southeast of Seoul, Xinhua reported.
Prime Minister Chung Hong-won attended the brief send-off ceremony along with South Korean Cardinal Andrew Yeom Soo-jung.
Before his departure, the Pope presided over the last Mass at Myeongdong Cathedral in Seoul. President Park Geun-hye was invited to attend the Mass, where the pontiff delivered a message of peace and reconciliation.
Prime Minister Chung Hong-won attended the brief send-off ceremony
Also invited were seven Korean women forced into sex slavery at the Japanese military brothel during World War II, and other socially isolated people, such as laid-off workers of Ssangyong Motor and residents of Mirayng, the southeastern city where the state-run power provider plans to build high-voltage transmission towers.
Pope Francis on Saturday conducted a large open air mass in Gwanghwamun Square in Seoul to beatify 124 of South Korea's first Catholics.
He paid tribute to the Koreans, who died for their faith in the 18th and 19th centuries, and who were the founders of the church in the region
Francis Saturday met families and survivors of the Sewol ferry disaster. Around 170,000 people were invited to the Mass, and some one million people were estimated to have participated in the Mass.
Pope Francis had arrived in Seoul on Thursday.