ANC provincial chairman Senzo Mchunu was sworn in as acting premier by KwaZulu-Natal Judge President Chiman Patel in Durban.
Mkhize said his tasks as ANC treasurer general had prompted the decision.
“After considering the workload associated with my two responsibilities, I have come to the conclusion that I need to spend more time fulfilling my responsibilities as the treasurer general of the African National Congress.”
Mkhize was elected treasurer general at the ANC’s elective congress in Mangaung last year.
He praised Mchunu and his colleagues in the KwaZulu-Natal executive.
He also thanked President Jacob Zuma for his support.
Mkhize would be based at ANC headquarters Luthuli House in Johannesburg full time as from September 1.
He said he believed the ANC would “start all the necessary processes” to ensure that a new premier was appointed by September 1.
Mchunu was appointed in an acting position until August 27 while Mkhize travelled with Zuma, who was scheduled to visit Malaysia.