Spyridon was born Spyridon Vlachos in 1873 in Chele, Bithynia, Asia Minor. He studied in the Theological School of Chalki and was assigned to serve in Kavala, where he supported the Macedonian Struggle. In 1906, he became Metropolitan of Vella and Konitsa. In 1916 he was elected Metropolitan of Ioannina and, in 1949, Archbishop of Athens and all Greece. His election to the archbishopric of Athens was unanimous.
As Archbishop of Athens, Spyridon worked for the reorganisation of the Church after the troubles of World War II and the Greek Civil War. He also supported the struggle of EOKA in Cyprus playing a leading role until Cyprus Archbishop, Makarios III, took over the reigns.