In 1999, he was selected for his first Rugby World Cup campaign, where he started in every game; including their 47–26 quarter-final defeat to France.

Ahead of the 2003 Rugby World Cup, where Argentina failed to advance past the group stage, Ledesma signed with Castres Olympique.

By 2005, he earned over 35 caps for Argentina and 80 professional appearances at French club level, and later signed with Clermont Auvergne ahead of the newly formed Top14 competition.

Clermont also made their first appearance in a French final since 2001, only to lose to Stade Français 23–18, after a 78th minute try by Radike Samo.

That same year, Argentina made it to the semi-finals of the 2007 Rugby World Cup, after topping their pool with victories over hosts France (17–12) and Ireland (30–15).

Ledesma also helped his side advance to the knock-out stage of the 2009–10 Heineken Cup, although lose to Leinster 29–28 in the quarter-final.

Ledesma was one of the leaders of Los Pumas' pack, and helped his side finish the pool stage 2nd, losing only to England.

In January 2015, Ledesma rejoined his former coach Michael Cheika, and joined the New South Wales Waratahs Super Rugby franchise ahead of the 2015 season.

[4] He joined the side as a set-piece consultant, and by March 2015, just a month into the season, the Waratahs scrum made great strides.

In July 2015, Ledesma followed Cheika to the Wallabies, after being appointed as forwards coach ahead of the 2015 Rugby World Cup.

It was the scrum that helped the Wallabies claim the 2015 Rugby Championship title and top their pool in the World Cup, with victories over England and Wales.

With wins over Scotland and Argentina in the quarter and semi-finals, the Wallabies made their first World Cup final since 2003, where they faced the All Blacks; who won the game 34–17.

Argentina could have finished third place at the end of the Championship after leading Australia in the final round 31–7 at half time.

After a winless campaign during the 2021 Rugby Championship, there have been numerous calls for his resignation, and on 9 February 2022, it was announced that he had left his post as head coach.