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In the Roman period, Mtarfa was a suburb of Melite, and it contained a Temple of Proserpina. The ruins of the temple were destroyed in the 17th and 18th centuries and the stones were reused in other buildings. Substantial remains of the suburb itself, including the arrangement of the streets and many tombs, survived until the late 19th century. In 1890, British military barracks began to be built in Mtarfa, destroying most of the Roman remains in the process.

A chapel dedicated to St. Lucy was first recorded in 1460, and is still standing to date. It is not currently in regular use.

A clock tower, now a prominent landmark of Mtarfa, was built in 1895. A naval hospital, RNH Mtarfa, was built during World War I, and it has now been converted to a state secondary school, named after Sir Temi Zammit. A chapel dedicated to St. Oswald was built by the British after the end of World War I.

Mtarfa was formerly part of Rabat local council, when local councils were first set up in Malta in 1993. In 2000 Mtarfa elected its first local council, after an amendment was made to the Local Councils Act.

Mtarfa was declared an Autonomous Pastoral zone in 2000, and became an independent parish in the denomination of the Roman Catholic Church on 8 December 2004. The parish church is also dedicated to Saint Lucy.