Vicente del Bosque's side was in fine form as it brushed aside the challenge of La Celeste, with goals from Pedro and Roberto Soldado sending it top of Group B.
The reigning world and European champion was in complete control and won over local fans with its stylish soccer seeing them find the net twice in the first half through Pedro and Roberto Soldado. Though the crowd became frustrated at times, the Europeans took their foot off the gas but an exquisite Luis Suarez free kick late on proved just a consolation.
Vicente del Bosque elected to start with Iker Casillas in goal for his side, despite the keeper not appearing for Real Madrid since January. The 62-year-old also opted to begin with Soldado in attack and the Valencia man almost repaid his coach's faith within five minutes, however he was unable to turn Jordi Alba's cross in at the back post.
La Roja monopolized possession in the opening stages and in the 10th minute a quick attacking injection caught Uruguay off guard. Andres Iniesta's dummy let the ball roll through to his Barcelona teammate Cesc Fabregas, who was denied a goal when his low shot crashed against the foot of the post.
Oscar Tabarez's men were struggling to cope with the crisp, interlinking passing of the Spaniards in the final third. It took two attempts for Fernando Muslera to keep out an effort from Iniesta after a lovely move at the top of the box six minutes later.
It seemed an inevitability that Spain would find the net and that is precisely what happened in the 20th minute. Pedro's sublimely-struck effort looked to be heading for the bottom corner but a deflection off of Lugano made sure it found the net by redirecting it past the already-committed Muslera.
Uruguay began to rile its opponent and almost stole a goal through Edinson Cavani with a well-worked free kick routine, but the World Cup holder re-asserted itself by doubling its advantage soon after.
A tremendous disguised pass from Fabregas picked out Soldado with space to take a touch on the edge of the area before guiding the ball past Muslera confidently just after the half-hour mark.
Spain's relentless pressing made it difficult for Uruguay to get any respite and it took a brilliant reflex save from its keeper in order to keep out Gerard Pique's header before the break.
After the interval it was more of the same from la Roja, as Soldado and Iniesta both came close to adding their team's third but neither was able to pull a save from Muslera.
There was less urgency from Del Bosque's men in comparison to the first half but their incessant passing was stopping Suarez and Cavani from having any impact on the game. A tame volley from Pedro in the 64th minute that went wide of the post was their only subsequent effort.
They certainly paid the price as Suarez conjured up a moment of sheer magic when he bent an immensely-precise free kick inside Casillas' near post from in excess of 25 yards, but la Roja held on in a nervy end to the game.
Victory ensures Spain goes to the top of the Group B with three points but that could change depending on the result of tomorrow's fixture between the group's other contenders, Nigeria and Tahiti.