[4] In October 2018, Premier Helen Zille appointed Winde to the post of Provincial Minister of Community Safety.

On 8 May 2019, the Democratic Alliance retained their majority in the Western Cape Provincial Parliament, but with a decrease in the number of seats.

Winde started many small businesses that specialised in printing, selling bicycles, courier services and boat parts in Knysna.

[10] Shortly after being elected a district councillor, the Democratic Party recruited him to be a candidate for the Western Cape Provincial Parliament.

[11] Premier Helen Zille appointed Winde to the position of Provincial Minister of Finance, Economic Development and Tourism following his re-election in May 2009.

[21] Winde has served as acting Premier of the Western Cape on various brief occasions when Zille was unavailable.

[22] Winde emerged as the front-runner quite early on in the Democratic Alliance selection process for the party's candidate for Western Cape Premier.

[23] On 19 September 2018, Democratic Alliance Federal Leader, Mmusi Maimane, announced Winde as the party's candidate to succeed Zille after the 2019 elections.

Winde defeated prominent candidates such as the Provincial Leader of the Democratic Alliance in the Western Cape, Bonginkosi Madikizela, and Member of Parliament David Maynier in an internal party vote.

[24] The Democratic Alliance won a majority in the Western Cape Provincial Parliament, but with a decrease in the number of seats, on 8 May 2019.

[25] Winde was elected Premier of the Western Cape on 22 May 2019 during the first sitting of the Sixth Provincial Parliament and accordingly became the second Democratic Alliance member to hold the office.

His main challenger for the post was Cameron Dugmore of the African National Congress, who received 10 out of the 34 valid votes.

However, Winde wrote to President Cyril Ramaphosa and Defence Minister Nosiviwe Mapisa-Nqakula in mid-September 2019 to request that the SANDF deployment in Cape Town be extended,[30] stating that it was necessary to bring stability.

[32][33] Winde delivered his maiden State of the Province Address on 18 July 2019, in which he highlighted the provincial government's achievements and outlined his agenda.

[42] On 22 October 2021, Public Protector Busisiwe Mkhwebane found that Winde and the Provincial Minister of Local Government, Environmental Affairs and Development Planning, Anton Bredell, had breached the Executive Ethics Code over their handling of issues at the Oudtshoorn Local Municipality.

[47] Winde and the provincial minister of health, Nomafrench Mbombo, then organised a media briefing about the province's preparedness.

[50] As positive cases in the province started to climb, Winde released daily detailed updates on the spread of the virus.

[54] As the province began to experience its "second wave" of infections in early-December 2020, Winde said that there should be harsher penalties for people who violate the regulations.

"[62][63] On 15 March 2022, Winde condemned the Minister of Co-operative Governance and Traditional Affairs, Nkosazana Dlamini-Zuma's decision to extend the State of disaster for another month.

[64] On 26 August 2023, DA leader John Steenhuisen announced that Winde was the party's Western Cape premier candidate for the 2024 provincial election.