[1] As of 1 November 2024, he is also serving as the cabinet secretary in the ministry of interior, albeit in an acting capacity, succeeding Prof. Kithure Kindiki who was appointed Deputy president following the impeachment of Rigathi Gachagua.

In May 2012, Mudavadi resigned from his role as Minister of Local Government to contest for the presidency in the 2013 Kenyan general election where he finished third.

After his late father Moses S. B. Mudavadi, he is the only other Kenyan politician who does not swear oaths of office because his faith forbids it.

[6] In 2005 Mudavadi made a political comeback by joining Raila Odinga's Liberal Democratic Party ( LDP) and aligning himself with the 'No' side in that year's Referendum on the proposed new Constitution amidst speculation that he was set to become the leading Luhya politician.

But after the ODM-K split, Mudavadi joined the Orange Democratic Movement (ODM) where he rose to the Deputy Party Leader.

A violent post election crisis developed, which eventually led to the signing of a power-sharing agreement (National Accord) between Kibaki and Odinga.

Briefly, he joined Uhuru Kenyatta and William Ruto to form the Jubilee Coalition bringing together UDF, URP and TNA parties.

Mudavadi objected saying the joint candidate had been agreed upon by consensus and that the partners in the Jubilee Coalition were new and did not have bonafide delegates selected through grassroots elections.

Keenly aware of the configuration of Kenyan elections, Mudavadi formed the National Super Alliance (NASA) coalition and invited the CORD trio of ODM's Raila Odinga, Wiper's Kalonzo Musyoka and Ford-Kenya's Moses Wetang’ula to join.

[13] In March 2021 Mudavadi strategically aligned with the other two NASA Principals Kalonzo Musyoka and Moses Wetang’ula, and KANU Chairman Gideon Moi, to form the One Kenya Alliance (OKA).

[citation needed] On September 27, 2022, President William Ruto issued and signed a Presidential executive order establishing the office of the Prime Cabinet Secretary of the Republic of Kenya,[15][16] and nominated Mudavadi to the position.

In March 2010, Deputy Prime Minister Musalia Mudavadi faced investigation by the Kenya Anti-Corruption Commission (KACC) over a Sh283 million cemetery land fraud.

In June 2020 according to court records as reported by the Daily Nation, Mudavadi did not benefit from cemetery land deal thus was not culpable in the scandal.

In addition, Mudavadi is an ardent fan of old school country music with Kenny Rodgers and Dolly Parton being his favourite musicians.