With seven countries now potentially set to represent South America at the 2026 World Cup, both nations will be expecting to qualify.
Match preview
For Uruguay, navigating the gruelling CONMEBOL format again will see them reach a fifth consecutive World Cup finals for the first time.
In each edition of qualifying for the World Cups between 2002 and 2014, Uruguay finished fifth in the playoff spot, meaning on each occasion they had to play an intercontinental playoff - one of which they lost to Australia in 2006.
Their last two qualifying campaigns have been much more convincing though, remarkably finishing second in 2018 and third behind Brazil and Argentina in reaching the Qatar finals.
The competitive and ruthless nature of CONMEBOL qualifying makes any slip-up very costly, especially on home soil, which is so often such a huge advantage in South America, so anything but a win here in their opener would be a huge let-down for Uruguay.
Uruguay are still unbeaten in 2023, drawing against Japan before recording three straight victories over South Korea, Nicaragua and Cuba, with Marcelo Bielsa coming in as manager for the latter two of those wins.
Bielsa's job will be to make Uruguay as competitive as they were in the 2010s, following a surprise group stage exit in Qatar.
The two-time World Champions have often suffered greatly since being semi-finalists in 1970, winning just one finals match in the 40 years that followed.
A semi-final appearance in 2010, progressing ahead of Italy and England in 2014's 'group of death' and a quarter-final in 2018 was very respectable for a country of Uruguay's size, though.
Their showing in Qatar fell well below expectations, though, and cost Diego Alonso his job, opening the door for Bielsa to make his return to the international stage, becoming just the second non-Uruguayan to take charge after Daniel Passarella did in 2000.
Chile will travel to Montevideo with a woeful run of away form lingering over them, as they have failed to win in all of their previous eight matches outside of their home country.
Manager Eduardo Berizzo must rectify that form if they want to contend for the qualifying spots after two successive failures to reach the finals.
Their last two qualifying campaigns have yielded just four wins combined, a big factor in them missing out on qualification.
The days of the mid-2010s golden era seem a lifetime away now, where Chile pushed hosts Brazil all the way to penalties in the knockouts at the 2014 World Cup, before winning back-to-back Copa America titles in 2015 and 2016.
A 7-0 quarter-final thrashing of Mexico in the 2016 edition helped them on the way to seal a second successive penalty shoot-out win over Argentina in the final.
Argentina though, along with Colombia and Peru, prevented Chile from reaching Russia 2018 on the final day of qualifying, and that has since led to a sharp decline.
Finishing with a defeat at home to Uruguay saw them end 2022 qualifying with just 19 points from 18 games, but they still finished seventh, a position that would earn them a playoff spot this time around.
Berizzo has since arrived as manager, but even though form has picked up in 2023, he started with losses to South Korea, Tunisia, Ghana, Morocco and Poland, while only drawing with Qatar and Slovakia.
Uruguay form (all competitions):
L
W
D
W
W
W
Chile form (all competitions):
L
D
W
W
W
D
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Team News
Uruguay have been struck by numerous injuries to many of their key players, including Barcelona defender Ronald Araujo.
Rodrigo Bentancur, Giorgian De Arrascaeta and Matias Vecino will also be big misses in midfield, with the trio absent through injury as well.
Bielsa will look towards new Paris Saint-Germain man Manuel Ugarte to provide a combative presence in the midfield, along with Real Madrid's Federico Valverde.
Luis Suarez and Edinson Cavani have not been selected since their World Cup exit, leaving Liverpool's Darwin Nunez with huge shoes to fill, but he has started the season very well.
Lucas Torreira, Sebastian Coates and Jose Maria Gimenez are among the notable omissions from the squad.
Chile's legendary trio of Alexis Sanchez, Arturo Vidal and Gary Medel remain in the squad and could all feature again to add to their combined total of 451 international caps.
Charles Aranguiz is also chasing down a milestone, with the former Bayer Leverkusen midfielder just three games away from reaching 100 caps.
Ben Brereton Diaz has made a slow start with struggling Villarreal in La Liga, but he often finds form for Chile, like he did during the 2021 Copa America, and he should partner Sanchez up top.
Veteran keeper Claudio Bravo is possibly no longer in the plans of Berizzo as he has been left out, with Gabriel Arias the most likely candidate to start between the sticks.
Eugenio Mena, Javier Altamirano and Damian Pizarro have all pulled out with injury, along with Bruno Barticciotto, who scored twice on his international debut against the Dominican Republic in June.
Uruguay possible starting lineup:
Rochet; Puma Rodriguez, Caceres, Vina, Olivera; Valverde, Ugarte, De La Cruz; Pellistri, Gomez, Nunez
Chile possible starting lineup:
Arias; Delgado, Medel, Maripan, Suazo; Pulgar, Valdes, Aranguiz, Vidal; Sanchez, Brereton Diaz
We say: Uruguay 2-0 Chile
Uruguay have never lost a home game against Chile in their international history and will fancy their chances of keeping up that record with a win here, despite some key injuries.