Mpande was born in Babanango, Zululand, the son of Senzangakhona kaJama (1762–1816) and his ninth wife Songiya kaNgotsha Hlabisa.

His defeat at the hands of the Boers led to unrest, which Dingane attempted to control by eliminating potential successors such as Mpande.

Fearing he would be killed if he joined Dingane, Mpande instead led thousands of Zulus into the Boer republic of Natalia.

The Boers led by Andries Pretorius and Gert Rudolph decided to support Mpande, hoping to gain concessions if he could oust Dingane.

In October 1843 British commissioner Henry Cloete negotiated a treaty to define the borders of Natal and Zululand.

Mpande also negotiated with the Boers, ceding land around the Klip River in 1847, which the British considered a violation of the treaty.

The massacre produced a large influx of refugees into Natal led by his aunt Mawa kaJama; according to British colonial official Abraham Josias Cloëté, nearly all kraals as far north as Nseleni had been deserted.

[2][3] Mpande adopted an expansionist policy in the early 1850s, initially raiding the areas surrounding the Zulu kingdom.

According to historian Philip Bonner, Mpande wanted Swaziland to be under his control because of fears of Boer expansion from Natal.

[9] Colenso's associate, Zulu convert Magema Fuze, gave a Biblically inspired account of the history of the Zulus in his book The Black People and Whence they Came.

In this account God punishes wicked rulers like Shaka and Dingane, but the Zulus flourish under "Mpande's peaceful, enlightened rule."

[10] H. Rider Haggard's Allan Quatermain novel Child of Storm is set during the power struggle between Cetshwayo and Mbuyazi.