Born in Las Rosas, Santa Fe, Ponzio started his career in the youth system of Newell’s Old Boys in neighbouring Rosario, going on to make more than 100 official appearances for the club. At only 21, he was signed by Real Zaragoza for the 2003–04 season, for €3 million. After making his La Liga debut on 31 August 2003 in a 0–1 home loss against Deportivo de La Coruña, he went on to become an essential midfield figure for the Spanish side, only missing 11 matches in three seasons combined.

Ponzio played for Argentina at under-17 and under-20 levels, and received his first full cap in 2003. In 2001 he played all seven matches (five complete) as the national team won the FIFA U-20 World Cup, on home soil.

However, when Zaragoza finished sixth in the 2006–07 campaign and qualified to the UEFA Cup, Ponzio had already left, moving in January 2007 to Club Atlético River Plate. He scored his first goal for his new team in the 2007 edition of the Copa Libertadores, against Chile’s Colo-Colo.

In January 2009, Ponzio returned to Zaragoza signing a four-and-a-half-year contract, with the club now in the second division. He contributed regularly as the team returned to the top flight immediately.

Ponzio was an ever present defensive figure in 2009–10, inclusively featuring at right and left-back, while collecting 15 yellow cards. He scored his only goal of the season on 3 April 2010, striking from long range in a 2–0 home success against Málaga CF.

On 4 January 2012, aged 30, Ponzio, whose link in Aragon ran until June, left struggling – in sporting and financial terms – Zaragoza and returned to River Plate for personal reasons, agreeing to a three-and-a-half-year deal.