Soderling, only competing in the elite year-end showpiece at London's O2 Arena because of the withdrawal of Andy Roddick, backed up his opening Group B victory over Rafael Nadal with another magnificent display to all but seal a semi-final spot.
Djokovic looked disgruntled throughout the one hour 34 minute contest and offered token resistance after losing the first set.
Soderling, this year's French Open runner-up, had never beaten Djokovic in five previous clashes with the Serb and punched the air with delight after his opponent netted a lame volley on match point.
Djokovic, the defending champion after winning the year-ender in Shanghai last year, will need to re-group quickly for his final round-robin match against Nadal on Friday.
Nadal plays his second round-robin match later on Wednesday against Davydenko with both players seeking a first victory.
Soderling replaces injured Roddick at ATP finals
Andy Roddick on cruise control
Spotted: Rafael Nadal in Chennai
Murray and Federer through in Madrid
Del Potro gets off the mark at World Tour Finals