The vote 461 in favour, 157 against and 89 abstentions was unsurprising, since she had already cleared the hurdles with European Union (EU) lawmakers in recent days, Xinhua news agency reported.
Von der Leyen's start, since being named to the post of president by leaders of the 28 EU member states, was shaky. She struggled through her first vote in the European Parliament, winning by only nine votes in her own confirmation, after which several of her nominations of new European commissioners were defeated by lawmakers, leading to weeks of delay in taking office.
Von der Leyen delivered a speech before the vote on Wednesday. Now the European Council has to approve the Commission by a qualified majority before it takes office on December 1.
In her speech, von der Leyen repeated her pledges, such as a geopolitical European Commission, strong actions on climate change and strategic autonomy.
"This is an unsettled world, where too many powers only speak the language of confrontation and unilateralism," von der Leyen said, stressing that "the world needs our leadership more than ever."
"Countries from east to west, from south to north, need Europe to be a true partner," she said. "We can be the shapers of a better global order. This is Europe's vocation. And it's what European citizens want."
"My Commission will not be afraid to speak the language of confidence and assertiveness. But we will do it our way, the European way," she said. "This is the geopolitical Commission that I have in mind and that Europe urgently needs."
The term "geopolitical" has become von der Leyen's oft-used term, and it is understood to mean that the bloc will be more active in external affairs.
Strahinja Subotic of the think tank European Policy Center (EPC) wrote in an analysis that the European Commission will increase its focus on external action, that the position of its top diplomat will be strengthened, and that the rise of external actors in the western Balkans will be monitored more closely.
( With inputs from IANS )