Middleton was born in 1910 in Belfast. He trained at Belfast College of Art, he was heavily influenced by the work of Vincent van Gogh. He regarded himself as the only surrealist working in Ireland in the 1930s.
His work first appeared at the Royal Hibernian Academy in 1938. His first solo exhibition was at the Grafton Gallery in 1944. A damask-designer like his father before him, he now devoted himself to full-time painting. More exhibitions followed in Dublin, London and Boston.
In 1953, he moved to Bangor where he designed for the New Theatre; he also designed sets for the Circle Theatre and the Lyric Theatre. At around this time he exhibited alongside Daniel O'Neill at the Tooth Galleries in London. In the same year (1954), he started his career as an art teacher at the Belfast College of Art and at Coleraine Technical School, eventually becoming head of art at Friends' School, Lisburn. The 'Dublin Magazine' at this time said of him: 'Apart from the brilliance of his paint, he has one rare quality in his inexhaustible capacity for wonder'.
A poet and musician, Middleton also produced murals, mosaics and posters. In 1969, he was awarded an MBE and appointed an associate at the Royal Hibernian Academy, with full membership in 1970. A major retrospective was held in 1976 at The Ulster Museum and the Hugh Lane Municipal Gallery of Modern Art in Dublin. He continued to exhibit at the RHA in Dublin until his death in 1983 in Belfast.
- John Hewitt, Colin Middleton (Arts Council/An Chomhairle Ealaíon and the Arts Council of Northern Ireland, 1976)