Born in Scotland on 15 June 1792, he was son of John Mitchell of Carron Works and was brought up from childhood by his uncle, Thomas Livingstone of Parkhall, Stirlingshire. On the death of his uncle, he joined the British army in Portugal as a volunteer, at the age of sixteen. On 24 June 1811, at the age of nineteen, he received his first commission as 2nd Lieutenant in the 1st Battalion 95th Rifles (later the Rifle Brigade / Royal Green Jackets). Utilising his skills as a draughtsman of outstanding ability, he was occasionally employed in the Quartermaster-General's department under Sir George Murray.

Mitchell's fourth expedition was into Queensland in 1845-46. He was convinced that a significant river must flow north-west into the Gulf of Carpentaria, this being the main thrust of the endeavour.  On 15 December 1845 Mitchell started from Boree (Buree in Mitchell's journal) with a large party including Edmund Kennedy as second in command (later speared to death at Escape River near Cape York). He struck the Darling River above Fort Bourke then continued to the Narran River, the Balonne, and the Culgoa. On 12 April 1846 he came to a natural bridge of rocks on the main branch of the Balonne which he called St.George Bridge, now the site of the town of St George. Kennedy was left in charge of the main body here, and was instructed to follow on slowly while Mitchell pushed ahead with a few men. Mitchell followed the Balonne to the Maranoa, and the Cogoon (now called Muckadilla Creek, near Roma). This rivulet led him to a magnificent pastoral district in the midst of which stood a solitary hill that he named Mount Abundance. He then crossed a low watershed to the Maranoa and awaited Kennedy's arrival. Kennedy rejoined Mitchell on 1 June 1846.  Leaving Kennedy for a second time, he set out on an extensive excursion of more than four months. Mitchell traversed the country at the head of the Maranoa and discovered the Warrago River. Keeping north over the watershed, he traversed the Claude and Nogoa rivers, then reached the Belyando River, an upper reach of the Burdekin River. This had already been discovered by Ludwig Leichhardt on his expedition to Port Essington on 2 April 1845. Intensely mortified to find that he was on a tributary of the Burdekin River, and approaching the ground already trodden by Leichhardt, he returned to the head of the Nogoa and struck west, after dividing his party and forming a stationary camp. He continued west, making a new discovery which he was certain was the fabled north-west river. In honour of the sovereign of the time he decided to call it Victoria River. Having run out of time, he turned back towards the main party. It was here that Mitchell first noticed the well known grass that bears his name. On the homeward journey he trekked along the Maranoa River to St.George Bridge, arriving in Sydney 20 January 1847. Later that year, Kennedy proved beyond doubt that the Victoria did not continue north-west, but turned south-west and joined Cooper Creek. He renamed the watercourse the Barcoo River from a name mentioned by local Aborigines.

Was he correct?
Later that year, Kennedy proved beyond doubt that the Victoria did not continue north-west, but turned south-west and joined Cooper Creek.