[6][7] Zikalala joined the African National Congress (ANC) in 1990 and became a full-time organiser for the party in Ndwedwe between 1993 and 1994.

Zikalala was a member of the party's Million Meyiwa Branch and served as ANC Zonal Chairperson from 1995 to 1996, before his election to the ANCYL North Durban Regional Executive Committee later on in 1996.

[9] Zikalala was elected ANC Provincial Chairperson on 8 November 2015 after he defeated incumbent Senzo Mchunu by a margin of 105 votes.

[10][11] He was sworn in as a Member of the KwaZulu-Natal Legislature on 26 November 2015 and consequently filled the vacancy created by the resignation of Super Zuma.

Following his swearing-in as an MPL, opposition parties staged a walkout of the legislative chamber over Zikalala's decision to sit in the seat that is traditionally reserved for the Premier.

[12][13] On 6 June 2016, the newly elected Premier of KwaZulu-Natal, Willies Mchunu, appointed Zikalala to the position of MEC for Economic Development, Tourism and Environmental Affairs.

[20][21][22] 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.

The Democratic Alliance, an opposition party, subsequently accused him of abusing his position by asking Ramaphosa to grant Zuma a pardon.

[27] During a law enforcement operation on Bayhead Road leading to the Durban Harbour on 13 January 2022, Zikalala condemned the proliferation of counterfeit goods.

[31] 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.

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.

[43] On 11 August 2022, Dube-Ncube announced that Zikalala had been appointed as the Member of the Executive Council for Cooperative Governance and Traditional Affairs.

[45][46] On 21 December 2022, it was revealed that Zikalala had received the most votes from party delegates to the National Executive Committee, and had thus secured a seat on the NEC as an additional member.