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His political experience started with the Italian Socialist Party, where he was elected to the municipal council of Venice. He got elected for the first time to the Italian Parliament in 1976 and was elected again in 1979, 1983, 1987, 1992 and 2006. He was Minister for State's Participation from 1980 to 1983. He then became Minister of Work in 1986 (with Bettino Craxi as President of the Council). His career however reached the top with his nomination to the Vice-Presidency of the Council in 1988-1989. He became Minister for Foreign Affairs in 1989 and kept that post until 1992.
Between 1993 and 2001, during the so-called "judicial storm of Mani Pulite", was accused of curruption along with many of the socialists MPs and regional administrators. Within more than 35 different trails, apart from the numerous favorable verdicts, he has been convicted of corruption and was sentenced to 1 year and 6 months (negotiated) in Venice for highways bribes in Veneto and to 6 months for illegal financing (Enimont bribe, also negotiated).
His leadership however had been contested in the congress of October 2005 where the son of Bettino Craxi, Bobo Craxi claimed to have been declared secretary after De Michelis had left the hall declaring the Congress void. This led Bobo to open a judicial case. The judge, on the second verdicts, gave unquestionably confirmed the right to use the symbol and the secretacy to Gianni De Michelis.