Sargent was born into a family that had dwelled in the town of Stamford in South Lincolnshire for more than five centuries. Though a coal merchant by profession, his father also served as church organist and choirmaster. It was decided at an early age that young Malcolm, too, would pursue a career in church music. In 1909, the 14-year-old boy was unexpectedly asked to fill in for an absent conductor at a local rehearsal of Gilbert and Sullivan's The Gondoliers, making quite an impression.

At 16, Sargent took the associateship diploma of the Royal College of Organists and was sent as an apprentice to the organist of Peterborough Cathedral. In 1914, he received his bachelor of music degree from Durham and became parish organist of Melton Mowbray, where Sargent quickly began to set up community musical activities. Sargent served in the 27th Durham Light Infantry during World War I and upon discharge took his doctorate of music (Durham again) and became a pupil of pianist Benno Moiseiwitsch. In 1921 Sir Henry J. Wood invited Sargent to conduct his own Impression on a Windy Day (Sargent's first and only real venture into composition) at a Promenade Concert in London. By 1923, Sargent had joined the teaching staff of the Royal College of Music.

In 1924, he served as chief conductor of the Robert Mayer children's concerts, and for two seasons, beginning in 1926, led the D'Oyly Carte Opera Company in London. He served as assistant conductor for the Ballet Russe's London seasons in 1927 and 1928. Never forgetting his foundation in choral music, Sargent accepted leadership of the Royal Choral Society in 1929 (a post he held for the next 20 years) and the Huddersfield Choral Society in 1932. In that same year, he helped Beecham found the London Philharmonic Orchestra. Between 1939 and 1957, he held chief conductorships with the Hallé Orchestra, the Liverpool Philharmonic, and the BBC Symphony Orchestra. From 1948 until the year before he died, Sargent organized and conducted the Promenade Concerts in London.

Sargent gave the premieres of three Vaughn Williams operas (Hugh the Drover, 1924; Sir John in Love, 1929; Riders to the Sea, 1937), as well as Holst's At the Boar's Head in 1925 (with the recently founded British National Opera Company). Sargent introduced Walton's Troilus and Cressida at Covent Garden in 1954.

Frequent touring introduced Sargent's uniquely energetic brand of music-making to a wide audience around the world (including the U.S.S.R., South Africa, and the Far East). In 1947, he was knighted for his conspicuous service to British music. He firmly believed that the works of Elgar, Walton, and Delius would eventually take their place alongside the great classics of Western art music. Sargent used guest appearances with the NBC Symphony as an opportunity to expose American audiences to a wide range of British composers.

He maintained a hectic schedule, and yet somehow found time to maintain a variety of extra-musical interests; the breadth and depth of his knowledge was revealed when he became a member of the BBC Brains Trust during the war. Sargent never lost touch with his rural roots (he in fact founded a symphony orchestra in Leicester) and his down to earth attitudes to music came as a breath of fresh air to many listeners tired of the weary, pedantic approach of many serious musicians. A firm believer in fundamental musical intent as opposed to superficial accuracy, Sargent was not loathe to alter a musical score in instances when he felt an advancement in instrument technology made a better realization of the composers intent possible.