Merkouris was born in 1856. He was first elected Mayor of Athens in 1899 and remained in office until 1914. In 1917, he was accused of having taken part in the "November events" (riots against supporters of Eleftherios Venizelos' Komma Fileleftheron) and was exiled to Corsica. He returned in 1920 when the Popular Party of Dimitrios Gounaris came to power.
Spyros Merkouris was the grandfather of actress-activist Melina Mercouri who called him "the most influential person in her life".