While both sides cruised through the group stage, negotiating the first knockout round proved a tougher task, and they now meet for the first leg of their last-eight tie at Estadio Monumental de la UNSA.
Match preview
Trailing by two goals following the first leg in Santiago, the prospects of Internacional reaching the Copa Sudamericana quarters looked slim as they welcomed Colo Colo to Estadio Beira-Rio last month, and when they went further behind in the 15th minute it seemed they were heading for elimination.
Summoning up some resilience, though, Inter fought back to reduce their deficit to one by half time, and Pedro Henrique's 74th-minute strike eventually secured a remarkable 4-3 aggregate victory over the Chilean club.
Head coach Mano Menezes, who was appointed in April, has since steered his side to a run of just one defeat in seven games - a 2-1 Campeonato Brasileiro loss to league leaders Palmeiras.
Following a 3-0 win over reigning champions Atletico Mineiro on Sunday, where Inter gave up most of the ball but were ruthlessly efficient on the counter, the Porto Alegre side sit sixth in the Serie A table; just a point adrift of the top four.
Though they ultimately seek a return to the Copa Libertadores via a high league finish, attention now turns to South America's second-tier tournament, which the club last won in 2008.
Having seen his team both lose and draw two of their four most recent away matches, though, former Brazil boss Menezes will now be aiming for a win on Thursday, to take a lead back to Brazil.
However, Melgar may prove a tough nut to crack in their home city of Arequipa, as they have won all four of their fixtures there during this season's Copa Sudamericana campaign.
After a goalless draw in the first leg of their last-16 tie, Pablo Lavallen's side posted another victory in front of their own fans by beating Colombia's Deportivo Cali 2-1 last month, to secure progress to a first-ever continental quarter-final.
Indeed, Los Rojinegros had never reached the knockout rounds before this year, and are relative minnows on such a stage.
Recent winners of the Peruvian Primera Division's Apertura phase, losing only three times in 18 matches, Melgar only occupy sixth spot in the early Clausura standings, but have a game in hand on most teams above them.
Three 1-0 wins from their last four league outings suggests they are primed to host one of South America's biggest names this week, as they aim to keep the quest for silverware alive.
Melgar Copa Sudamericana form:
Melgar form (all competitions):
Internacional Copa Sudamericana form:
Internacional form (all competitions):
Team News
Internacional's hopes of a positive first-leg result have been boosted by the return of captain Taison and his former Shakhtar Donetsk teammate Alan Patrick to full training this week - both could now feature on Thursday.
Mano Menezes had been unable to call upon the attacking duo for nearly a month due to thigh injuries, but their comeback coincides with Mauricio's best performance of the season - the 27-year-old scored twice in the win over Atletico-MG on Sunday, and was named man of the match.
Another option up front will be new signing Braian Romero, who made his debut at the weekend, but Caio remains out of action with an ankle problem.
Melgar, meanwhile, will turn to top goalscorer Bernardo Cuesta to lead the line up front, and the hosts' skipper - who scored both goals against Deportivo Cali in the last round - will be supported by winger Luis Iberico.
Up against challenging opposition, Los Rojiblancos are expected to set up in a 4-2-3-1 formation at Estadio Monumental, with former Peru goalkeeper Carlos Caceda providing their last line of defence.
Melgar possible starting lineup:
Caceda; Ramos, Galeano, Deneumostier, Reyna; Arias, Tandazo; Iberico, Guedes, Bordacahar; Cuesta
Internacional possible starting lineup:
Daniel; Bustos, Vitao, Mercado, Rene; Gabriel, Edenilson; Wanderson, Patrick, Henrique; Mauricio
We say: Melgar 0-1 Internacional
Despite some good results of late, Melgar have found the net only five times in their last eight matches, so could find themselves out of their depth against experienced opponents.
Perhaps over-reliant on captain Cuesta, the hosts may be heading to Porto Alegre next week with a deficit to retrieve.