Alexis Sanchez netted a double and Lionel Messi scored his usual goal as the reigning European champions survived a scare early in the second half when Michal Kadlec headed home to put one foot into the quarter-final stages.
After just over 40 minutes of toying with Leverkusen, Barcelona took the lead when Messi played a clever ball with the outside of his foot from the centre of the pitch into the path of Sanchez and the Chilean took one touch into the area before slotting underneath Bernd Leno for his first Champions League goal in his first Champions League start for Barca.
After an extremely poor first half, Leverkusen came out firing in the second term and managed to get back on level terms when Vedran Corluka hung up a dangerous cross from the right for Kadlec to rise above his opponents to head home from the six-yard box for his first ever goal in the competition.
However, minutes later, Barcelona were back in front when Sanchez raced on to a beautiful pass from Cesc Fabregas to round Leno and then knock it home into an open goal to restore his side's advantage.
With two minutes remaining, Barcelona grabbed a third when Messi played a great ball to Dani Alves who waited to whip a cross back into the path of the Argentine maestro who side-footed home with veritable ease to wrap up the first leg.
There were a plethora of great chances for both sides in the second half with Valdes coming up with a vital one-handed save when Renato Augusto shot on target in the 57th minute before Leverkusen were agonisingly close to a second when Gonzalo Castro saw his fierce effort from the left side of the area tipped onto the far upright by trhe Barcelona gloveman.
With just under 20 minutes left, Messi almost produced a customary piece of magic when he took on a couple of defenders outside the area before attempting a cheeky dink over Leno but he could not sneak it past the near post.
Again Leverkusen came close in the 78th minute when substitute Stefan Kiessling got on the end of Castro's curling cross but his header was not enough to beat Valdes who held safely on the goal-line before Sanchez was denied a hat-trick late in the match when Leno produced a super save from his powerful header.
Pep Guardiola's men dominated Robin Dutt's charges for most of the 90 minutes indicating that the Germans will find it extremely difficult to overcome the two-goal deficit (and three away goals) when n the return leg at the Nou Camp on March 7.
UEFA Champions League Round of 16 - first leg
BayArena, Leverkusen - 30,210