The RAF received its first Wellesleys in April 1937, serving with No.76 Squadron at Finningley, and eventually equipped six RAF Bomber Command squadrons in the UK. Five aircraft with provisions for three crew members were modified for long-range work with the RAF Long-Range Development Flight. Additional modifications included the fitting of Pegasus XXII engines and extra fuel tanks. On 5 November 1938, three of them under command of Squadron Leader Richard Kellett flew non-stop for two days from Ismailia, Egypt to Darwin, Australia (7,162 mi/11,525 km) setting a world distance record. All three aircraft succeeded in breaking the existing record, but No. 2 aircraft landed in West Timor, 500 mi (800 km) short of the final objective. The Wellesley's record remained unbroken until November 1945. This flight is still the longest by a single engined aircraft.
By the outbreak of the Second World War, the Wellesley had been phased out from home based squadrons, with only four examples remaining in Britain, but remained in service with three squadrons based in the Middle East. Following the Italian declaration of war on 10 June 1940, the remaining Wellesley squadrons became involved in the East African Campaign against Italian forces in Eritrea, Ethiopia, and Somaliland. Although obsolete, the Wellesley formed a major part of the British Commonwealth's available bomber forces, mainly carrying out raids against Eritrea and Northern Ethiopia. Sudan-based Wellesleys carried out their first bombing mission on 11 June 1940 against Asmara in Eritrea. Three days later they were involved in their first air combat. Capitano Mario Visintini, future top scoring biplane ace of the Second World War, intercepted a pair of Vickers Wellesleys from 14 Squadron, bound to bomb Massawa. Visintini, who was flying a Fiat CR.42, shot down the aircraft K7743, flown by Pilot Officer Reginald Patrick Blenner Plunkett. It was the first of Visintini's 16 air victories in Eastern Africa. In the early part of the campaign, fighter escort was not available, and when caught by CR.42s, Wellesleys proved vulnerable to the Italian biplane fighter. Despite this, the Wellesley continued to be used for bombing raids, bombing Addis Ababa from Aden on 18 August. The Wellesley continued in use against the Italians over East Africa until November 1941, when Gondar, the last Italian-held town, fell to Commonwealth and Ethiopian forces. The final Wellesley equipped unit, 47 Squadron was then switched to carrying out maritime reconnaissance duties over the Red Sea, continuing in this role until September 1942.
While the Wellesley was not a significant combat aircraft, the design principles that were tested in its construction were put to good use with the Wellington medium bomber that became one of the main types of Bomber Command in the early years of the European war.
In February 1940, three Wellesleys (K7728, K7735 and K8531) were sold to Egypt to serve in the Royal Egyptian Air Force.