After some occasional appearances at the local radio station, he and his family moved to Rio in 1951. Under the pseudonym of Carlos José, he appeared in the most famous radio show of that time, the Programa César de Alencar. With the help of his mother, he recorded his first single (as an interpreter, not as a composer), which he put under his arm and offered to all radio stations and recording labels of Rio. It was when he met Valdemar Henrique, composer and folklorist, who worked at the Rádio Roquette Pinto, who opened for him the possibility of presentation in some shows. He also became acquainted with Ed Lincoln and Luís Eça, who were playing at the Plaza nightclub and let him sit in during the band's breaks. Enrolling in law school, he became an activist, joining the Popular Culture Center of the National Students Union (CPC da UNE), centers where civil society resisted culturally. There he met Carlos Lyra, whose social concerns led him to abandon bossa nova and find a new venue for expression. Together, they were the creators of the genre later known as "canção de protesto" (protest song). Vandré's first compositions were in partnership with Lyra: "Quem Quiser Encontrar o Amor" (recorded by Lyra on an 78 rpm in April 1961, through RGE) and "Aluanda."

In 1962, the Philips LP O Sambalanço de Carlos Lyra brought "Quem Quiser Encontrar o Amor," and the song was also included in the movie Cinco Vezes Favela, produced by the CPC. In the same year, he became acquainted with Baden Powell, Luís Roberto, and Vera Brasil, starting a series of presentations with them at the famous João Sebastião Bar in São Paulo. With singer Ana Lúcia, he recorded "Samba em Prelúdio" (Baden Powell/Vinícius de Moraes) with great success and which opened for him the bossa nova doors. His "Pequeno Concerto que Virou Canção" delved even deeper in the bossa waves, but he split with the movement, deciding to research his roots and produce music coherently with his origins. The first result was the toada "Canção Nordestina" (Northeastern Song). In those times, the bossa was presented in informal places and would only gain the formal acknowledgment of theaters a while after. So, he presented it at the Colégio Mackenzie during a bossa event and the song had an impact. He married Nilce Tranjan, who gave him strong support in his initial career, in 1964. His first LP, recorded still in that year (December, through Audio Fidelity) had "Fica Mal com Deus," but found no success. In the next year, he was commissioned by moviemaker Roberto Santos to write the soundtrack to Santos' A Hora e a Vez de Augusto Matraga. In that same year, he performed at the I FMPB interpreting Chico Buarque' "Sonho de um Carnaval," classified in sixth place; he also recorded his second LP, Hora de Lutar. In 1966, he recorded the LP Cinco Anos de Canção, which had a partnership with Baden Powell, "Rosa Flor." Also in that year, he won first place at the FNMP with the marcha-rancho (written with Fernando Lona) "Porta-Estandarte," interpreted by Tuca and Airto Moreira. The victory opened the way for a signed contract with the Rhodia company, through which he would be financed to tour the Northeast with the then Trio Novo (Theo de Barros, violão; Airto Moreira, percussion; and Heraldo do Monte, Brazilian viola), who, at the end of the tour, were joined by Hermeto Pascoal, becoming the Quarteto Novo. Still in 1966, Vandré won the II FMPB (TV Record, São Paulo) with "Disparada" (with Theo de Barros), interpreted by the Trio Novo, Jair Rodrigues, and Trio Maraiá, tied with "A Banda" (Chico Buarque). In the same year, he also won second place at the I FIC (TV Rio, Rio) with "O Cavaleiro" (written with Tuca, who defended it). He was then so popular that he was commissioned by São Paulo's TV Record to write and host his own show, Disparada. He also hosted his own other shows, Canto Geral (after, Canto Permitido) on TV Bandeirantes and Caminhando (TV Globo). His subsequent participation at two festivals were unsuccessful: "Ventania" at the III FMPB and "Da Serra, da Terra e do Mar" at the II FIC. At the same time, his composition "Arueira" and the frevo "João e Maria" (with Hilton Accioly) made great success.

Commissioned by the Dominican priests of São Paulo, he wrote the music for the sacred drama "A Paixão Segundo Cristino." In 1968, he recorded the album Canto Geral (Odeon). He inscribed "Bonita" (with Accioly) at the IV FMPB, with no success. At the III FIC, he protagonized one of the most emotional moments of MPB. Accompanied by the Quarteto Livre (Naná Vasconcelos, Franklin, Geraldo Azevedo, and Nelson Ângelo, all of them becoming famous artists), he defended his song "Caminhando -- Pra Não Dizer que não Falei das Flores." It was a favorite of the audiences, but the jurors elected for first place "Sabiá" (Chico Buarque/Tom Jobim). In a deeply passionate atmosphere, he told the public that it was only a festival and that there were more important things to worry about. He followed his interpretation of the song with the multitude singing in unison (the thrilling episode is registered on the 1996 compilation Vandré). The song became a sort of anthem of students and civil society, but was prohibited by censorship. Soon after the AI-5 (an act that granted dictatorial powers to the military government) was decreed, Vandré was exiled. He stayed out for four years, time spent in Chile (where he composed "Desacordonar," being expelled from the country under the pretext of having presented himself on national TV without proper documentation), France, Algeria, Germany (where he recorded shows for TV), Austria, Greece, and Bulgaria, always performing in upcountry villages.

Sergio Endrigo recorded his songs. In 1970, he recorded in France with the Quinteto Violado the LP Terras do Benvirá, released in Brazil only in 1973, and re-staged A Paixão Segundo Cristino. In 1973, he recorded TV shows for exhibition in Brazil, but they were censored. In July, he returned to Brazil and in 1982, he performed in Puerto Stroessner, Paraguay, close to the Brazilian border. In March 1995, he was present at a concerto promoted by the CONAR (Army command unit). On that occasion, a choir of cadets performed "Fabiana," a song Vandré had written as an homage to the Brazilian Air Force (FAB), which confounded the Brazilian intelligentsia. Later, laconic interviews hadn't contributed to solve the mystery of such an astounding change of course, as his criticisms are directed only toward the cultural industry and he preferred to be silent about everything else. "This isn't the right moment to say what I know," in his own words. In 1997, the Quinteto Violado released the CD Quinteto Violado Canta Vandré (Atração), and Elba Ramalho, Geraldo Azevedo, and Zé Ramalho recorded "Disparada" and "Canção da Despedida" on their CD Grande Cncontro 2. His musical biography was released on the CD Vandré, in 1996 by RGE.