Makhura became the Premier of Gauteng in 2014 after succeeding Nomvula Mokonyane who went on to become a minister in the cabinet of Jacob Zuma. Makhura was the favourite of the provincial ANC leadership, which had in the past been opposed to President Jacob Zuma's leadership.
Crime
In 2014 after taking office Makhura said that the people of Gauteng needed to wage war on crime to protect their children while speaking at a meeting in the community of Reiger Park as part of the government's, Gauteng Township Economy Revitalisation Programme. Makhura spoke at Reiger Park after the shooting of four-year-old Taegrin Morris who had been killed in a botched hijacking the previous month. In 2016 Makhura laid charges against former head of the Department of Sport, Namhla Siqaza, in a bid to recover more than R800 million in government tenders that had improperly been awarded.
Health
In 2014 the newly built Natalspruit Hospital was officially opened and was christened as the "future of Gauteng Health" by Makhura. The Minister of HealthAaron Motsoaledi, who also attended the opening with Makhura, said that the equipment found inside the hospital was previously only found in private hospitals. The Natalspruit Hospital had cost R 1.7 billion to construct in a period of 8 years and was furnished with 821 beds. While addressing senior managers, CEOs of Gauteng hospitals, health workers and professionals at the 2016 Khanyisa Service Excellence Awards. Makhura said that although Gauteng had been the best-performing province in 2015, the province could do better. A survey suggested that 69% of people in Gauteng were satisfied with the provincial healthcare services. Makhura said that it was not good enough and was aiming for 80% satisfactory level by 2019. Makhura said that the Department of Health in Gauteng would spend more than R1.2 billion over three years on the modernisation of public health and R3 billion on equipment.
Employment
Makhura said that he had ambitions to grow the economy of the province, which will create employment for thousands of unemployed people in Gauteng.
Revitelisation of townships
Makhura said that the province was working on a concrete plan to revitalise old townships in the province. Makhura said that in order to change Human Settlements in five years the province was planning to build 140 000 houses around Gauteng. All those developments would have major socio-economic benefits with regard to decent employment and economic inclusion.
2019 re-election and second term
Following the May 2019 elections, the ANC announced that it had retained Makhura in his position of Premier of Gauteng. His second term as premier commenced on 22 May 2019, after he defeated the Democratic Alliance's Solly Msimanga for the post.
Personal life
On 10 July 2020, Makhura announced that he had tested positive for COVID-19, becoming the third premier in one week to test positive for the virus.