Commission chief and ex-Luxembourg PM Jean-Claude Juncker will not handle the probe, Margaritis Schinas said.
Pepsi and Ikea are among those accused of making deals with Luxembourg to save billions in tax in other countries.
The revelations were published in a report by the International Consortium of Investigative Journalists (ICIJ).
Luxembourg is already under investigation by the EU over suspected “sweetheart” tax deals with online retailer Amazon and the financing arm of carmaker Fiat.
Two other member states, Ireland and Malta, are also being investigated as part of the EU’s crackdown on multinationals’ tax avoidance schemes.
Luxembourg PM Xavier Bettel has insisted that the deals abided by international rules on tax, in comments reported by AFP news agency.
The ICIJ said a team of 80 journalists had pored over nearly 28,000 pages of leaked documents showing tax agreements and returns relating to more than 1,000 businesses.
It says the companies created “complicated accounting and legal structures that move profits to low-tax Luxembourg from higher-tax countries where they’re headquartered or do lots of business”.
In some cases, it adds, companies enjoyed tax rates of less than 1% on profits moved into the European duchy.
“The Duchy of Luxembourg has a legitimate government that has to provide answers to the investigation opened by the Commission,” the EU Commission’s spokesman Margaritis Schinas told reporters on November 6.
When pressed repeatedly about Jean-Claude Juncker’s role in the probe, Margaritis Schinas said that EU Competition Commissioner Margrethe Vestager would take charge of the current investigation.
“She will request the appropriate information, enforcing the rules, as is the duty of the European Commission,” he added.
The leaked papers related to some 340 companies, including FedEx, Accenture, Burberry, Procter & Gamble, Heinz, JP Morgan, Deutsche Bank.
The deals – which the ICIJ says were legal – were facilitated by the international tax advisory group PricewaterhouseCoopers.
The Guardian, which was one of the media outlets working on the probe, said it painted “a damning picture of an EU state which is quietly rubber-stamping tax avoidance on an industrial scale”.
Luxembourg was “like a magical fairyland,” the paper quotes former senior US Treasury official Stephen Shay as saying.
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