The first certain mention of his name occurs in 1612, in connection with an expedition in search of a Northwest Passage, under the orders of Captain James Hall, whom he accompanied as chief pilot. Captain Hall was killed in a fight with the local inhabitants on the west coast of Greenland, and during the two following years Baffin served in the Spitsbergen whale-fishery, at that time controlled by the Muscovy Company.

In 1615 he entered the service of the Company for the Discovery of the North-West Passage, and accompanied Captain Robert Bylot as pilot of the little ship Discovery, and now carefully examined Hudson Strait. The accuracy of Baffin's tidal and astronomical observations on this voyage was confirmed in a remarkable manner by Sir Edward Parry, when passing over the same ground, two centuries later (1821).

In the following year Baffin again sailed as pilot of the Discovery, and passing up Davis Strait discovered the fine bay to the north which now bears his name, together with the magnificent series of straits which radiate from its head and were named by him Lancaster, Smith and Jones Sounds, in honour of the generous patrons of his voyages. On this voyage he had sailed over 300 statute miles (480 km) farther north than his predecessor John Davis, and for 236 years his farthest north (about lat. 77° 45') remained unsurpassed in that sea.

All hopes, however, seemed now ended of discovering a passage to India by this route, and in course of time even Baffin's discoveries came to be doubted until they were re-discovered by Captain Ross in 1818. Baffin next took service with the British East India Company, and in 1617-1619 performed a voyage to Surat in British India, and on his return received the special recognition of the Company for certain valuable surveys of the Red Sea and Persian Gulf which he had made in the course of the voyage.

Early in 1620 he again sailed to the East, and in the Anglo-Persian attack on Kishm in the Persian Gulf, preparatory to the reduction of Ormus, he received his death-wound and died, January 23, 1622. Besides the importance of his geographical discoveries, Baffin is to be remembered for the importance and accuracy of his numerous scientific and magnetic observations, for one of which (the determination of longitude at sea by lunar observation) the honour is claimed of being the first of its kind on record.

Baffin Bay and Baffin Island are named in his honour.