An obscure former finance minister just five years ago, Vestager burst onto the global scene in 2014 by pushing competition cases against Google, Apple and Amazon, taking a far more aggressive tack than her predecessor.
Google rapidly accumulated eight billion euros ($8.8 billion) in fines, Facebook was admonished, while Amazon and Apple were ordered to pay huge sums in back taxes, the latter for a jaw-dropping 13 billion euros.
"She hates the United States perhaps worse than any person I've ever met," US President Trump told Fox News in June.
But opprobrium from the White House has helped make Vestager a star, with competition authorities around the world following in her footsteps in moves against big tech, including in the United States.
Rewarded for her work, Vestager will soon have more power than ever to hound alleged digital monopolists in the new commission announced Tuesday by EU president-elect Ursula von der Leyen.
Promoted to executive vice present, the darling of the Brussels bubble will effectively become Europe's grand-master of tech regulation, while still holding on to her powerful anti-trust portfolio.
But competition lawyers warn that the next five years may not be a seamless continuation of her success story, with opponents -- not only in Washington -- ready to do battle, most significantly in EU court.
"Commissioner Vestager often said that she would like to be in the job when her main cases were decided in court, and she has achieved this," said Alfonso Lamadrid, an antitrust expert at law firm Garrigues in Brussels.
"Their outcome might be decisive to assess the Vestager years," said Lamadrid, who does work for technology companies that have appealed EU decisions in court.
The court is a highly unpredictable place, and some landmark European Commission cases have been thrown out, most recently with a refusal by Brussels to greenlight the buyout of parcel shippers TNT by UPS.
Rumours always swirl around what the judges may decide, and chatter in Brussels is that the cases against Google and Apple face an uncertain fate.
"Predicting results in the EU court is a very risky business," said Thomas Vinje, a veteran anti-trust lawyer in Brussels who has taken on Google.
The EU's cases are strong, "but if the commission were to lose, that could very likely affect their willingness to pursue other cases," Vinje said.
Behind the scenes, some experts wonder whether Vestager's reputation as a slayer of big tech may be overblown.
"Despite the hoopla, Vestager has in fact had little very impact on digital markets in Europe. She's far too friendly to big tech and she lets them design their own remedies," tweeted Matt Stoller of the Open Markets Institute, which recommends competition policies.
"European enforcers are more talk than action," he added.
Lobbyists for big tech are in fact more afraid of another nomination to the commission team that takes office on November 1.
Former French defence minister Sylvie Goulard is set to take over the single market portfolio with responsiblity to draw up new legislation on how big tech platforms can do business in Europe.
The ambitiously named Digital Services Act will be the battle royale for lobbyists in the next months and years as worry runs deep that interventionist France and Germany may demand strict curbs on Amazon, Google and Facebook.
"With Goulard running the single market, things will get heated," a senior lobbyist said on condition of anonymity.
France and Germany meanwhile will keep a close eye on Vestager.
The EU's most powerful members, they are furious over her veto earlier this year of a Siemens and Alsthom rail business merger that they say denied the creation of a European champion in the industry, a gift to Chinese rivals.
They now demand deep reform of EU competition law, which Vestager said she would consider, but only after sounding out "many different voices".
"It is competition that creates the champions we need," she added in an interview with AFP on Tuesday.