In 1820 Clapperton removed to Edinburgh, where he contracted an intimacy with Dr Oudney, who first awoke his interest in the cause in which both were destined to perish. After the return of Captain Lyon, the British Government having determined on equipping a second expedition for the purpose of exploring Northern Africa, Dr Oudney was appointed to proceed to Bornu as consul, and Clapperton and Colonel Denham were added to the party. From Tripoli, early in 1822, they set out southward to Murzuk, and from this point Clapperton and Oudney travelled westward into the country of the Tuaricks, as far as Ghraat, 11° E. long. On the 17th February 1823 they reached Kouka the capital of Bornu, where they were well received by the sultan; and after remaining here till the 14th December they again set out for the purpose of exploring the course of the Niger. They arrived in safety at Murmur, where Oudney breathed his last in the arms of his companion. Clapperton, however, penetrated alone as far as Sackatu, 13° N. lat. and 6⅛ 0 E. long., where he was obliged to stop, though the Niger was only five days’ journey to the west. Worn out with travel he returned to Kouka, where he again met Denham. The two travellers then set out for Tripoli, and thence proceeded to England, where they arrived on June 1, 1825. An account of the travels of Denham, Clapperton, and Oudney was published under the title of The Narrative of Travels and Discoveries in Northern and Central Africa in the years 1822-24.

Immediately after his return Clapperton was raised to the rank of commander, and sent out with another expedition to Africa. He set sail in August 1825, in company with Captain Pearce, Mr Dickson, Dr Morrison, and Richard Lander, who acted as his servant. On this occasion he landed at Badagry in the Bight of Benin, and immediately commenced his journey into the interior, along with Lander, Captain Pearce, and Dr Morrison. The last two soon fell victims to the hardships of the journey; but in January 1826 Clapperton reached Katunga, the capital of Yariba, and soon afterwards crossed the Niger at Broussa, the spot where Mungo Park met his untimely fate. In July he arrived at Kano, a city which he had previously visited. Here he left his servant with the baggage, and proceeded alone to Sackatu, intending to proceed to Timbuctu. The sultan, however, detained him, and being seized with dysentery he died at Sackatu on the 13th April 1827. His Journal was published by Lander, who also wrote a work entitled Records of Captain Clapperton’s last Expedition to Africa, which appeared in 1830, in 2 vols. 12mo.