The diminutive midfielder continued his fine scoring run at his new club, a classy strike from the edge of the area giving him his sixth goal in his last five games in all competitions.
More importantly for coach Fred Rutten, it gave the hosts a winning start in a group which also includes Hapoel Tel Aviv and Rapid Bucharest.
PSV were on the front foot from the off as Mertens' 20-yard effort brought a smart parry out of Legia goalkeeper Dusan Kuciak.
At the other end Jakub Wawrzyniak tested Przemyslaw Tyton from long range.
But the hosts were the side in control and Tim Matavz blazed over the top from well inside the area.
PSV went in front in the 21st minute thanks to an excellent finish from Mertens.
The Belgium winger, a summer signing from FC Utrecht, hit an instinctive shot from the corner of the area which flew high into the net.
Jeremain Lens then had a shot blocked by Marcin Komorowski as Legia continued to live dangerously.
PSV conceded three second-half goals to lowly VVV-Venlo in the Eredivisie last weekend and Legia had their best chance in the opening minutes of the second half when Komorowski met Maciej Rybus' free-kick into the area, but his header went wide.
There was, though, little of the "lethal" counter-attacking threat Rutten warned his side of before the game as PSV, and Mertens in particular, remained the more menacing.
The Belgian was a persistent threat and his cross gave Matavz a sight of goal, but his header went over.
The Slovenia striker, another close-season acquisition, sent another header high as PSV aimed to put the result beyond doubt.
Danijel Ljuboja then shot over the bar from 30 yards as he looked to earn a point for the Polish side in stunning fashion, but Kuciak was soon called into action again to punch clear Stanislav Manolev's dangerous corner as PSV claimed victory.