The original idea for a mixed Catholic secondary school in Hounslow came from Fr. (later Canon) Musgrave in 1936. He was the Parish Priest of SS Michael and Martin's Church but his plans were delayed by the Second World War.
In 1952, two sites were offered, one near Green Lane and the second at 106 Bath Road which included an Orchard. Canon Musgrave died in 1955 and it was under his successor, Canon John Mackenzie, that building work began in 1958.
The School was to be known as Archbishop Myers Secondary School and was to accommodate 450 pupils. The first 279 arrived on 10th May 1960 and were welcomed by Headteacher Mr Patrick Boland and 11 staff. The builders remained until April 1961 and the School was officially opened in March 1962.
In 1972 the School became a Comprehensive and changed its name to St Mark's. The uniform changed from maroon to navy blue. Originally six forms of entry were planned with a split site - a Senior School located at the other end of Hounslow High Street. These plans were dropped and in 1978 the buildings of the old SS Michael and Martin's Primary School were included in the enlarged St Mark's site. The original Parish Church dating from 1886 became a Sixth Form Common Room.
Patrick Boland retired in 1978 and was replaced by Mr Patrick Topp. St Mark's now contained 800 pupils and 50 teachers. Mr Topp was succeeded by Mr David Sheath in 1986 and the School's popularity continued to grow. By the time of Mr Sheath's retirement the School was recognised as one of the best in the London area. Mr Paul Enright become Headteacher in 2001 and the School grew to over 1200 pupils. Under his leadership examination results became consistently outstanding and St. Mark's is recognised as being one of the top comprehensive schools in the country for Progress at GCSE. Following his retirement in August 2018 Ms Andrea Waugh-Lucas was appointed as the School's first female Headteacher in September 2018.