Born in KwaZulu-Natal, Mthethwa rose to prominence in the ANC Youth League and joined the National Assembly in 2002.

[2] Mthethwa became active in the students' anti-apartheid movement as a teenager, joining the Klaarwater Youth Organisation in 1982 and serving as its chairperson from 1987 to 1989.

[5] On 23 January 2008, the ANC removed Isaac Mogase as Chief Whip of the Majority Party in the National Assembly and appointed Mthethwa to replace him.

Mthethwa's role was scrutinised because of evidence that, in the days before the confrontation, he had taken phone calls with the SAPS operational command, with National Union of Mineworkers president Senzeni Zokwana, and with mining magnate and former politician Cyril Ramaphosa; Zokwana and Ramaphosa had reportedly expressed concern about the inadequate police response to the strike, which some observers inferred had led Mthethwa to exert pressure on SAPS to upgrade its response.

[15] However, though he confirmed that he had relayed Zokwana and Ramaphosa's concerns to the provincial SAPS commissioner, he denied that there had been political pressure for a harsh police response.

Judge Ian Farlam's final report on the commission's findings, published in 2015, did not recommend any remedial action against Mthethwa.

[18] In April 2012, City Press reported that the Hawks were investigating claims that Mthethwa had benefitted personally from a slush fund managed by the SAPS Crime Intelligence Division.

According to the City Press report, Mthethwa was attempting to suppress the Hawks investigation, which was being pursued by acting police chief Nhlanhla Mkhwanazi.

[24] As Minister of Police, Mthethwa was a central figure in the Nkandlagate controversy, which concerned the use of public funds to make major renovations, labelled security upgrades, to President Zuma's personal residence in Natal.

In addition, at the height of the public scandal, Mthethwa attempted to enforce a ban on taking photographs of the residence.

Although President Zuma retained Mthetwa in his second-term cabinet, he was moved to a new position in an apparent demotion, becoming Minister of Arts and Culture.

[32][33][34] He served in that portfolio for almost nine years: after the May 2019 general election, Zuma's successor, President Cyril Ramaphosa, retained Mthethwa in an augmented post as Minister of Sports, Arts and Culture.

[37][38][39] In January 2021, members of the industry circulated a social media petition titled #NathiMustGo after Mthethwa posted a Tweet which was perceived as minimising the harm of the COVID-19 pandemic to South African theatre.

[42] Defending the proposal in Parliament, Mthethwa said that the flag would promote social cohesion as "a monument for democracy in this country".

[53] Mthethwa's wife is Philisiwe Buthelezi, a businesswoman and the chief executive officer of the National Empowerment Fund.