George Guest was born in Bangor, Wales. His father was an organist, and George assisted him by acting as organ blower. He became a chorister at Bangor Cathedral, and subsequently at Chester Cathedral, where he received organ lessons from the sub-organist, Dr Roland Middleton. He passed the examination for ARCO in 1940, and FRCO in 1942. By this time he had become the organist and choirmaster of Connah's Quay parish church, Flintshire. George Guest was always proud of his Welsh roots and from the 1970s onwards took a personal interest in the Cambridge University Welsh Society (Cymdeithas Y Mabinogi), sponsoring many of its events and providing a welcome face for Welsh students away from home. At the age of 18 he was called up for military service, and joined the Royal Air Force, being posted to India in 1945. On leaving the services in 1947 he took up the post of sub-organist at Chester Cathedral. The cathedral organist, Malcolm Boyle, encouraged him to apply for the Organ Scholarship at St John's College, Cambridge, in which endeavour he was successful. At Cambridge he studied under Robin Orr. In his final year as Organ Scholar, Robin Orr announced that he intended to retire, and the College Council offered the post to Guest.

Within five years of Guest becoming Organist and Choirmaster, the whole future of the Choir at St John's College came into question, with the proposed closure of the day school which provided the Choristers. Guest, with the support of his predecessor, persuaded the College to found a Choir School. Under George Guest's direction, the choir built up a formidable reputation, challenging the supremacy of the choir of King's College, Cambridge. Guest introduced a more "continental" tone into the choir, as George Malcolm was doing at Westminster Cathedral. The choir began broadcasting on the BBC in the early 1950s, and recorded its first long playing record in 1958. By the time of Guest's retirement in 1991, the choir had recorded sixty LPs or CDs under his direction. The BBC has broadcast Evensong from St. John's College on every Ash Wednesday since 1972, and the Advent Carol Service each year since 1981. During George Guest's tenure, the choir undertook many overseas tours. In 1987 Guest was appointed Commander of the Order of the British Empire (CBE) in the Queen's Birthday Honours. Herbert Howells and Michael Tippett are among the many composers who wrote liturgical settings for the St John's College Choir whilst George Guest was Organist and Choirmaster. They also include the French composer Jean Langlais, who wrote a setting of the psalm Beatus vir for the choir: a rare occurrence of a Continental composer writing for the English Cathedral tradition. Speaking about the Choir, 'We are not', said Guest, 'the exponents of the hard face and the stiff upper lip. Our singing — we hope — is redolent of all the emotions'.