Edinson Cavani and substitute Christian Stuani were on target in each half in Montevideo as Uruguay extended their unbeaten streak on home soil.
Cavani opened the scoring in the 37th minute, glancing his header into the back of the net - his seventh goal in 10 competitive games for the national team.
And Stuani, who netted the winning goal against Northern Ireland on Saturday, come off the bench to put the result beyond doubt 13 minutes from time.
Uruguay have not lost at home since their 1-0 defeat to Argentina in a World Cup qualifier back in 2009, while Slovenia slumped to back-to-back defeats following March's 2-0 loss to World Cup participants Algeria.
Oscar Tabarez's Uruguay will now fly out to Brazil, where they will face Italy, England and Costa Rica in Group D.
As for Slovenia, who failed to qualify for the World Cup after finishing third behind Switzerland and Iceland in Group E, they are set to remain in South America as they prepare to take on Argentina on Saturday.
Uruguay coach Tabarez made just one change to the team that beat Northern Ireland, with Atletico Madrid defender Diego Godin replacing Liverpool's Sebastian Coates at the heart of defence.
In that match, Uruguay were guilty of making a slow start but that was not the case against the Slovenians.
The home side almost took the lead in the 11th minute when Forlan whipped in a teasing free-kick that took a deflection and forced goalkeeper Samir Handanovic to tip the ball away for a corner.
Uruguay then switched off and were fortunate not be trailing a minute later following a terrific run inside the penalty area from Josip Ilicic.
The Fiorentina midfielder drove past two defenders and towards the by-line before squaring the ball to Andraz Kirm, who sent his shot over the bar from close range.
Slovenia began to take control of possession as the half wore on but they were still suspect defensively, with defender Maxi Pereira going close to breaking the deadlock in the 24th minute courtesy of a cross-cum-shot that flashed off the crossbar.
Despite failing to make any significant impact on the match, it was Cavani who broke the deadlock eight minutes before the break.
Slovenia struggled to clear their lines and Forlan pounced, picking out Cavani on the edge of the six-yard box with a well-weighted lofted cross, and the 27-year-old headed Uruguay into a half-time lead.
With an eye on Uruguay's World Cup opener against Costa Rica on June 14, Tabarez rang the changes at the interval.
Stuani, Jorge Fucile, Alvaro Gonzalez and Jose Gimenez all came on in place of Gaston Ramirez, Pereira, Walter Gargano and Godin.
It did not hamper Uruguay's performance in the second half and they were unfortunate not to double their lead just past the hour mark, when Martin Caceres had a header saved on the line by Handanovic.
Stuani almost got himself on the scoresheet again but his audacious overhead-kick was tipped over the bar.
The Espanyol striker was not to be denied, however, tapping home a rebound in the 77th minute after Handanovic scrambled Cavani's initial effort.
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