Yepes has played 102 matches for the Colombia national team since his debut in 1999, making him the second-most capped Colombian player of all time, after Carlos Valderrama.
He was part of the Colombia squad that won the Copa América in 2001.
and was also in the squads for three other editions of the tournament in 1999,  2007 and 2011.

During the team's 2014 FIFA World Cup qualifying campaign, Yepes made 12 appearances as Colombia qualified for its first finals since 1998.
In the final qualifying match, Yepes scored both goals in a 2–1 victory against Paraguay.

Due to his age during the 2014 World Cup qualifiers, Yepes expressed his passion for the national team and wanting to retire either after the World Cup qualifiers or during the 2014 World Cup.
José Pékerman promised to meet with his retirement request.
On 17 December 2013, Yepes announced that he would retire after the 2014 World Cup.

On 14 June 2014, Yepes made his first appearance in the FIFA World Cup finals stage at age 38, captaining Colombia to a 3–0 win over Greece in Belo Horizonte.
Yepes was the oldest outfield player at the 2014 World Cup, and the second-oldest overall, after compatriot Faryd Mondragón.

On 19 June 2014, Yepes earned his 100th cap for Colombia in the second group stage match against the Ivory Coast, becoming the third Colombian player to reach the milestone after Valderrama and Leonel Álvarez.
He led Colombia to its best ever World Cup performance as they reached the quarter-finals for the first time in their history, where they lost 2–1 to tournament hosts Brazil.
Yepes has played 102 matches for the Colombia national team since his debut in 1999, making him the second-most capped Colombian player of all time, after Carlos Valderrama. He was part of the Colombia squad that won the Copa América in 2001. and was also in the squads for three other editions of the tournament in 1999,  2007 and 2011.
During the team's 2014 FIFA World Cup qualifying campaign, Yepes made 12 appearances as Colombia qualified for its first finals since 1998. In the final qualifying match, Yepes scored both goals in a 2–1 victory against Paraguay.
Due to his age during the 2014 World Cup qualifiers, Yepes expressed his passion for the national team and wanting to retire either after the World Cup qualifiers or during the 2014 World Cup. José Pékerman promised to meet with his retirement request. On 17 December 2013, Yepes announced that he would retire after the 2014 World Cup.
On 14 June 2014, Yepes made his first appearance in the FIFA World Cup finals stage at age 38, captaining Colombia to a 3–0 win over Greece in Belo Horizonte. Yepes was the oldest outfield player at the 2014 World Cup, and the second-oldest overall, after compatriot Faryd Mondragón.
On 19 June 2014, Yepes earned his 100th cap for Colombia in the second group stage match against the Ivory Coast, becoming the third Colombian player to reach the milestone after Valderrama and Leonel Álvarez. He led Colombia to its best ever World Cup performance as they reached the quarter-finals for the first time in their history, where they lost 2–1 to tournament hosts Brazil.
Mario Yepes