Fernando Torres opened the scoring in the 12th minute, but the world and European champions were pegged back just before half-time by a superb strike from South Korea midfielder Kim Do-Heon.
Betis midfielder Benat and Malaga full-back Nacho Monreal played despite being left out of Spain's final squad for Euro 2012.
Barcelona played in the Copa del Rey on Friday so their players were rested, though they are likely to play in the friendly against China on Sunday.
Torres had a great chance in the fifth minute when he attempted to divert Cazorla's shot into the bottom left-hand corner, but his instinctive volley whistled just wide.
The Chelsea striker was not to be denied for long and he opened the scoring with a lovely finish six minutes later. Mata crossed from the left, and the 28-year-old backheaded the ball over South Korea’s debutant goalkeeper Kim Jin-Hyun.
But Spain kept up the pressure, with Mata exchanging passes with Torres on the edge of the box, then the 24-year-old midfielder tried to find Silva with a threaded pass, but Kim Jin-Hyun was alert to the danger and quick to come out of his goal to grab the ball.
Spain really should have had a second on 41 minutes, when Silva found Torres with a lovely threaded pass, but the Chelsea striker then passed to an offside Mata rather than take the chance himself.
And Choi Kang-hee’s men took advantage of Spain’s profligacy a minute later, when the ball dropped to Kim Do-Heon on the edge of the box, and the 29-year-old slammed the ball right-footed into the top corner past Reina.
But South Korea gave away two goals in a matter of minutes after the break from a couple of handballs.
In the 51st minute, Cho Yong-Hyung turned his back from a Raul Albiol shot on the edge of the area, but left his hand dangling, and the referee awarded a penalty and a yellow card.
Xavi Alonso made no mistake from the penalty spot for his 13th goal in his 95th appearance, with a penalty low to the keeper's right.
Four minutes later, it was 3-1 after Albiol’s snapshot was this time handled by South Korea goalscorer Kim Do-Heon, and Cazorla’s low free-kick right on the edge of the area went though the wall and into the bottom corner of the goal.
South Korea had a great chance to get back into the game on 69 minutes when Kim Do-Heon slipped the ball through to Kim Bo-Kyung along the line of the penalty area, but the 22-year-old flicked the ball wide of Reina’s goal.
Negredo made it 4-1 in the 80th minute with a low finish underneath the goalkeeper Kim Jin-Hyun for his sixth goal in nine appearances.
The Sevilla forward’s goal was made by Valencia striker Roberto Soldado, who was left out of the 23-man selection for the Euros despite his fine league form and his hat-trick against Venezuela in the friendly in March.
It was a good outing for Spain, who open their Euro 2012 campaign against Italy on June 10, before facing Ireland four days later and then Croatia on June 18.