Born in Presidente Prudente, São Paulo, also having Italian origins, Zago moved to Dourados, Mato Grosso do Sul as a teenager, and began his senior career with local side Ubiratan, as a forward and being known as Tonhão.

[2] Upon arriving at São Paulo, Zago was known as Antônio Carlos, and was pushed back to midfielder by manager Cilinho.

He was later moved further back to a libero by the reserves manager Pupo Gimenez,[3] and made his first team debut on 25 April 1990 by starting in a 2–0 Campeonato Paulista away win over Portuguesa.

After the arrival of Telê Santana as manager, Zago established himself as a regular starter, winning two Campeonato Paulista (1991 and 1992), aside from lifting the 1991 Série A and the 1992 Copa Libertadores.

On 7 December 1995, Palmeiras agreed the transfer of Zago and teammate Edílson to Japanese club Kashiwa Reysol, for a combined fee of R$ 5 million.

[8] In January 1998, Zago moved to the Italian capital to join Roma for a fee of US$4 million,[9] at the request of the club's manager Zdenek Zeman, who was looking to reinforce the team's defensive line.

In his Serie A debut with the club, on 11 February 1998 at Lecce, he was sent off after only a few minutes of play; his performances with the giallorossi soon improved, however, and he was able to demonstrate his quality and skill, leading to him being recalled to the Brazilian national side in 1999.

Due to his success and performances with Roma, Zago still remains a popular figure with the romanista fans, who nicknamed him Terminator during his time at the club.

[10] In November 1999 Zago was the protagonist of a shocking episode, when he spat on Lazio player Diego Simeone's face during a derby match.

[21] He missed eight matches between September and October after serving a 45-day suspension,[22] and renewed his contract for the following season on 8 November,[23] as his side subsequently finished seventh.

[27] However, Palmeiras ended the 2010 Paulista with five winless matches under Zago, and after an alleged fight with player Robert, he was dismissed on 18 May.

[35] On 16 October 2013, he was appointed by FC Shakhtar Donetsk as their new assistant manager, joining his former Beşiktaş coach Mircea Lucescu.

[37] He finished second in the 2016 Campeonato Gaúcho with the club, knocking out Grêmio in the semifinals, and also achieved promotion in the 2016 Série C. On 11 December 2016, Zago announced his departure from Ju.

[51] On 31 October 2023, Zago was officially announced as Bolivia national football team new head coach, replacing the sacked Gustavo Costas.