Prempeh emerged as the new Asantehene in 1888, after a civil war over the succession that followed the death of his predecessor. He inherited a polity weakened by territorial secession, internal rivalry and British interference. His first major political achievement was the reunification of the member states of the Asante Union.

Within three years, Prempeh had restored the union and persuaded Dwaben to return. This revival alarmed the British, who feared both the recovery of Asante power and the possibility that French or German influence might replace their own. British officials offered to place Asante under their protection, but Prempeh firmly and politely rejected the proposal.

Prempeh followed his rejection by invading Nkoransa, Moa and Abease in 1892. When the British demanded a Resident at Kumasi and annual stipends for the Asantehene and other rulers, he refused and sent a large diplomatic mission to the Queen of England. The mission left Kumasi in November 1894, reached Cape Coast on 10 December, and departed for England on 3 April 1895.

The British government refused to receive the mission and issued an ultimatum while it remained in England. When Prempeh refused the British demands, an expedition under Sir Francis Scott entered Kumasi in January 1896. Prempeh and his advisers had decided not to fight, partly because they believed surrender would preserve the lives and tranquillity of their people.

Despite this decision, Prempeh, his mother, his uncles and several war chiefs were arrested and deported. They were sent first to Sierra Leone and later to the Seychelles in 1900. His exile symbolized the transformation of British protection into the effective destruction of Asante political independence.