Klitschko never looked in danger of losing his WBA, IBF, WBO and IBO belts, with the Ukrainian toppling the overmatched Thompson in the sixth.
Klitschko had already dropped the 40-year-old with 20 seconds left in the fifth, before finishing off the fight in the next.
It was the second win over Thompson for Klitschko, with the 36-year-old having stopped him in the 11th round four years ago.
Thompson had started the fight brightly with Klitschko struggling to find his range at the Stade de Suisse in Berne.
However, from the second round onwards it was all Klitschko, with Thompson unable to make an impact.
A win for Thompson (now 36-3) always seemed unlikely but as soon as a big right sent him to the canvas in the fifth it was only a matter of time before Klitschko closed out the win.
It wasn't the best of finishes for Klitschko, as Thompson was bundled back to the deck in the sixth but the American was slow to his feet - with the referee waving a halt to the bout.