Following the May 2019 elections, Zikalala was selected as the party's KwaZulu-Natal Premier candidate, succeeding
Willies Mchunu. He was elected to the office on 22 May 2019, and officially assumed the post on 27 May 2019. Following his inauguration, he announced his
Executive Council, which consisted of youthful members. On 8 July 2021, Zikalala admitted that the incarceration of former president
Jacob Zuma would hurt the ANC's electoral chances in the
November 2021 municipal elections. He commended the former president for handing himself over and said that he has never betrayed Zuma. Zikalala suggested that president
Cyril Ramaphosa should consider granting Zuma a
Presidential Pardon. The
Democratic Alliance, an opposition party, subsequently accused him of abusing his position by asking Ramaphosa to grant Zuma a pardon. Zikalala called on Zuma supporters to refrain from violence as pro-Zuma protests turned violent. On 15 July 2021, he was filmed allegedly assaulting an individual during the
unrest in KwaZulu-Natal. During a law enforcement operation on Bayhead Road leading to the
Durban Harbour on 13 January 2022, Zikalala condemned the proliferation of
counterfeit goods. He said that it was tantamount to economic sabotage. Zikalala said that the
police had confiscated an estimated R1-billion worth of counterfeit goods over the past year. Zikalala also called on the freight and trucking industry to prioritise employing South African truck drivers instead of hiring foreign nationals to avoid conflict. In March 2022, Zikalala called for a review of South Africa's
constitutional democracy and advocated for a move towards a
parliamentary democracy. Zikalala's call was described as a "dangerous, populist call steeped in political expediency". In April 2022, days of heavy rainfall caused
deadly floods in KwaZulu-Natal which damaged critical infrastructure in the province and led to the deaths of more than 300 people. After a late emergency meeting of the provincial executive council on 12 April 2022, Zikalala asked for a declaration of emergency so that the provincial government could gain access to emergency funding. On 13 April, a provincial state of disaster was declared in KwaZulu-Natal by the National Disaster Management Centre, which Zikalala welcomed. During the State of Emergency declared after the deadly floods, he controversially admitted that a water tanker delivered water to his personal residence to fill up the water tank on the premise. He vowed that it would never happen again - and that the tanker would be positioned at the local community hall for residents to retrieve water during the crisis. On 23 July 2022, Zikalala was defeated in the election for ANC provincial chairperson by MPL
Siboniso Duma. He received only 665 votes to Duma's 930 votes. Members of Zikalala's "Ankole"
slate also lost to members of Duma's "Taliban" faction in the elections for other provincial leadership positions. After the election results were announced, the newly elected provincial chairperson Duma said that Zikalala would not be removed as premier anytime soon. Zikalala was not re-elected to the
provincial executive committee. On 5 August 2022, Zikalala's intention to resign as premier of KwaZulu-Natal became apparent. He had told the ANC provincial leadership of his decision to step down, which they accepted. Zikalala resigned as premier on the same day. He was replaced by the MEC for Finance,
Nomusa Dube-Ncube on 10 August. ==Later political career==