Alex Baena scored the game’s only goal in the 42nd minute when his tame effort slipped through the hands of Uruguay goalkeeper Fernando Muslera.
The victory means Spain will face either Austria or Algeria in the Round of 32 in Los Angeles on Thursday.
Uruguay’s exit also confirmed World Cup debutants Cape Verde as Group H runners-up after they played out a goalless draw with Saudi Arabia, setting up a knockout meeting with Lionel Messi’s Argentina.
The two-time world champions became the highest-ranked team to be eliminated in the group stage after managing only two draws and one defeat.
The disappointing campaign came amid reports of unrest within the Uruguay camp, with several senior players, including Real Madrid midfielder Federico Valverde, reportedly disagreeing with head coach Marcelo Bielsa over his tactics.
Speaking after the match, Bielsa accepted responsibility for the team’s early exit.
“Journalists and fans of Uruguayan football legitimately want to pin the blame on me. I’m the person responsible and I have to accept it,” he said.
Spain, watched by King Felipe, struggled to create clear chances despite dominating possession.
Coach Luis de la Fuente admitted his side had not produced its best attacking display but praised the players’ discipline.
“In football, you can’t always play with the brilliance you wish for. We maintained an incredibly high level of concentration, responsibility and composure,” he said.
Spain were also dealt injury concerns after Yeremy Pino suffered a shoulder injury, while Nico Williams left the match with a muscle problem.
Veteran goalkeeper Muslera, who had also made costly errors in Uruguay’s 2-2 draw with Cape Verde, was substituted at half-time, while Valverde was withdrawn on the hour mark.
Ferran Torres came close to doubling Spain’s lead late in the game but struck the crossbar.
Uruguay’s frustrating campaign ended on a sour note when Agustin Canobbio was sent off in stoppage time for a reckless challenge on Pau Cubarsi.
Spain remain unbeaten in 34 competitive matches and have yet to concede a goal at the tournament, although their performances have fallen short of the attacking displays produced by favourites including France, Argentina and the Netherlands.
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