Fritz Wepper was born as the son of a Lawyer who was missing in action as a soldier in Poland in 1945. He started his acting career in a production of Peter Pan at the age of eleven. He got his first important film role in Tischlein deck dich, a film adaption of the Brothers Grimm fairytale The Wishing Table. His breakthrough role was as a young soldier in Bernhard Wicki's anti-war film Die Brücke (1959) which won the Golden Globe Award for Best Foreign Language Film. Wepper kept his popularity with German audiences into adulthood and appeared in several notable German films of the 1960s. In 1972 he played Fritz Wendel, a Jew passing as a Christian, in the Oscar-winning film version of Cabaret, opposite Liza Minnelli and Marisa Berenson.

His character Harry Klein, the assistant in the long-running crime series Derrick, became a cult figure all over the world. He played this role between 1974 and 1998 in 281 episodes of Derrick. Before playing Klein in Derrick he portrayed the same character on the popular television drama Der Kommissar (1969–1976) from the series' start until 1974 when he was transferred to Derrick. Harry Klein was replaced by his brother Erwin (played by Fritz Wepper's real-life brother Elmar Wepper).

Fritz and Elmar Wepper appeared together in the television series Zwei Brüder (1994-2000), playing a pair of different brothers hunting Criminals and solve difficult cases. Since 2002, Wepper plays the Tricky Mayor Wolfgang Wöller in the immensely popular TV series Um Himmels Willen (with some 7.2 million views per episode). Wepper married Angela von Morgan in 1979. His daughter, Sophie is also an Actress, they appear together in the crime series Mord in bester Gesellschaft since 2007. Wepper made headlines in the yellow press when he left his wife Angela for the younger Susanne Kellermann (born 1974) in 2009. He has a daughter (b. 2012) from the relationship with Kellermann, but later returned to his wife Angela.