Wetangula represented Sirisia Constituency in the National Assembly from February 2003 until January 2013. He was elected to the Senate of Kenya in 2013, representing Bungoma County, and became Minority Leader in the Senate.
Wetangula went to Nalondo Primary School, Busakala secondary school, Teremi Secondary School, and Friends School Kamusinga before being admitted to the University of Nairobi, where he graduated with a Bachelor of Laws (LLB) degree. He was a member of the Board of Directors of ICROSS Kenya from 1989, stepping down when he became Kenya's Minister for Foreign Affairs.
He was nominated as a Kanu MP after the 1992 general election, serving until 1997. He has held several other previous public positions which include that of magistrate and the chairman Electricity Regulatory Board. Wetangula actively participated in organisation of funds-drives to set up projects on self-help basis and has been offering legal services to the local people. He has mobilised women and the youth to initiate income generating projects.
Wetangula was elected to the National Assembly in the December 2002 parliamentary election. In the Cabinet appointed by President Mwai Kibaki on 8 January 2008, in the midst of a crisis regarding the results of the concurrent presidential election, Wetangula was named Minister for Foreign Affairs. Later in January, in reaction to criticism from the United Kingdom regarding the presidential election, Wetangula summoned the United Kingdom's High Commissioner, Adam Wood, to complain, and he said that "our elections don't need a stamp of authority from the House of Commons". After a power-sharing agreement was reached between Kibaki and Raila Odinga, both of whom claimed victory in the presidential election, Wetangula retained his post in the Grand Coalition Cabinet named on 13 April 2008.
In March 2012, Wetangula was stranded in Bamako, Mali during a coup d'état. He was evacuated after being trapped in his hotel room for several days.
Shortly after Wetangula's return, Kibaki shuffled his cabinet. Wetangula left his post as Foreign Minister and became the Trade Minister.
Wetangula left his ministerial post on 27 October 2010 due to ongoing investigation on his alleged involvement in the Kenyan Tokyo embassy scandal. It was alleged that instead of accepting free property from the government of Japan for the embassy, 1.6 billion shillings was withheld from the sale of Kenyan property in Nigeria and used to buy a less suitable property.
George Saitoti served as acting foreign minister during Wetangula's absence. He was absolved of the allegations and returned to the ministry in August 2011, though he permanently left the position a few months later to successfully contest for the position of Senator for Bungoma County.
After winning election to the Senate, Wetangula was selected to serve as Minority Leader of the Coalition for Reforms and Democracy. The Bungoma High Court nullified his election on 30 September 2013 and the Speaker of the Senate declared the seat vacant on 16 October 2013. In a by-election held on 19 December 2013, Ford Kenya candidate Moses Wetangula recaptured his Bungoma senatorial seat with a landslide win after garnering 149,458 votes against his main contender Musikari Kombo, who got about a half of the votes.
Kombo, who was vying on a New Ford Kenya ticket, came second with 81,016 votes followed by independent candidate David Makali and Labour Party of Kenya candidate Bifwoli Wakoli at a distant third and fourth place respectively.
Makali secured 2,155 votes while Wakoli garnered 1,899 votes from a total of 942 polling stations, with a 57 percent voter turnout.