Born in Terlizzi, province of Bari, South of Italy, as Nicola Vendola, he is commonly called "Nichi" (read Nee-Kee). He studied literature in university, presenting a dissertation about the controversial poet and movie director Pier Paolo Pasolini. He then went on to become a journalist for L'Unità, and a leading member of the Italian gay organisation Arcigay.

In 1992 he was elected to the Chamber of Deputies and has held his seat ever since. As a member of the Antimafia Commission, he came to prominence as a strong opponent of the Mafia and organised crime. In 2005, even though openly gay, he was elected President of Apulia Region.

Many moderates in the alliance criticised the choice, since it appeared impossible that a communist and homosexual could be elected president of a southern Italian region such as Apulia, generally considered to be conservative and strongly Catholic.

Vendola is also a poet: some of his poems have been collected in a book, named L'ultimo mare ("The last sea").