After leaving school, Mühe was employed as a construction worker and a border guard at the Berlin Wall. He then turned to acting, and from the late 1970s into the 1980s appeared in numerous plays, becoming a star of the Deutsches Theater in East Berlin. He was active in politics and denounced Communist rule in East Germany in a memorable address at the Alexanderplatz demonstration on 4 November 1989 shortly before the fall of the Berlin Wall. After German reunification he continued to appear in a large number of films, television programmes and theatre productions. In Germany he was particularly known for playing the lead role of Dr. Robert Kolmaar in the long-running forensic crime series Der letzte Zeuge (The Last Witness, 1998–2007).
The son of a furrier, Mühe was born on 20 June 1953 in Grimma, Bezirk Leipzig (part of present-day Saxony), in the German Democratic Republic (East Germany). After leaving school, he trained as a construction worker, then did compulsory military service in the Nationale Volksarmee (National People's Army) as a border guard at the Berlin Wall. He was relieved of duty after contracting stomach ulcers; possibly due to stress, according to observers, and also suggested that it marked the beginnings of the stomach cancer that would eventually lead to his death.
He then turned to acting, and studied at the Theaterhochschule "Hans Otto" Leipzig from 1975 to 1979. He appeared in his first professional stage role in 1979, as Lyngstrand in Ibsen's Fruen fra havet (The Lady from the Sea) at the Städtisches Theater in Karl-Marx-Stadt (now Chemnitz). He followed this by appearing in a production of Macbeth by playwright and director Heiner Müller at the Volksbühne in East Berlin.

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