While an experimental Mexican side saw off Bolivia in their first June friendly, an unfamiliar La Celeste lineup were held goalless by Costa Rica last time out.
Match preview
Despite naming a youthful starting XI, Mexico were able to secure a 1-0 win over Bolivia in Chicago last weekend, with a second-half strike from Efrain Alvarez proving enough to secure success in the first of three warm-up games for the Copa America.
El Tri will face Ecuador, Jamaica and Venezuela in Group B, and they have chosen to prepare with two tough tests over the next few days: after taking on Uruguay in Colorado, they must meet Brazil down in Texas.
Head coach Jaime Lozano is expected to recall several major players for both games, seeking to build more momentum after losing the recent CONCACAF Nations League final to the Mexicans' oldest foes, the USA.
That painful defeat continued Mexico's mixed run of results since the tail end of 2023, and Lozano's position has been called into question by fans and pundits alike.
Having led his nation's Under-23 team to a bronze medal at Tokyo 2020, the former Necaxa boss may need a similarly impressive finish in the Copa America if he is to survive the sack and build towards a World Cup partly hosted on home soil.
While Mexico play their tournament opener on June 23, against outsiders Jamaica, an ambitious Uruguay squad kick off their quest for a 16th continental title by meeting Panama one day later - Bolivia and hosts USA are their other opponents.
La Celeste's head coach, eccentric tactical maestro Marcelo Bielsa, is far more secure in his position than Lozano, though the Argentinian was absent for Saturday's 0-0 draw with Costa Rica.
Instead, Diego Perez, part of the Uruguayan coaching team that won the Under-20 World Cup last year, took charge of a selection featuring only uncapped players.
Discounting that result, as Bielsa's full squad will be back in action on Wednesday, Uruguay have scored in every game since their 2-0 loss to Portugal at Qatar 2022 and are sitting second in CONMEBOL's long World Cup qualifying series, having beaten both Brazil and Argentina.
In March, they suffered a 2-1 friendly loss to Ivory Coast - with the African champions inflicting Bielsa's second loss since taking over last year - but La Celeste remain well set to challenge for the crown this summer.
Mexico friendly form:
W
Mexico form (all competitions):
L
W
L
W
L
W
Uruguay friendly form:
D
L
D
Uruguay form (all competitions):
W
W
W
D
L
D
Team News
Now playing out the latter phase of his long and successful career at Boca Juniors, Uruguay's veteran striker Edinson Cavani surprisingly announced his retirement from international football last Thursday.
The 37-year-old was an integral member of his country's 2011 Copa America triumph, but now Liverpool's Darwin Nunez leads the line for La Celeste.
Jose Maria Gimenez captains the South American side from central defence; Manuel Ugarte and Rodrigo Bentancur should patrol midfield.
Meanwhile, stars including Ronald Araujo, record goalscorer Luis Suarez and recent Champions League-winner Federico Valverde have all been excused from Wednesday's game.
Mexico fielded no fewer than eight debutants last time out, with one - Ricardo Monreal - setting up the only goal against Bolivia.
However, Jaime Lozano will revert to a much stronger starting XI in Colorado, so Santiago Gimenez - scorer of 23 Eredivisie goals for Feyenoord last season - is set to start up front.
With 76 caps to his name, Edson Alvarez is El Tri's main man in midfield, while Genoa's Johan Vasquez should feature in central defence; experienced trio Jesus Gallardo, Hirving Lozano and goalkeeper Guillermo Ochoa have not been called up.
Mexico possible starting lineup:
Malagon; J. Sanchez, Montes, Vasquez, Arteaga; Chavez, Alvarez, E. Sanchez; Antuna, Gimenez, Vega
Uruguay possible starting lineup:
Rochet; Nandez, Caceres, Gimenez, Olivera; Bentancur, Ugarte, C. Araujo; Pellistri, Nunez, B. Rodriguez
We say: Mexico 1-2 Uruguay
Both teams fielded weakened teams last time out, but they will step up a gear or two in their penultimate pre-Copa America friendly.