The investigation centres around the company's 2011 acquisition of the fraught OPL 245 block, offshore Nigeria, by Eni and Royal Dutch Shell for $US1.3 billion ($A1.4 billion).
The acquisition took place when Descalzi was the head of the company's exploration and production division.
Chief development, operations and technology officer Roberto Casula is also under investigation.
"Eni is cooperating with the Milan prosecutor's office and is confident that the correctness of its actions will emerge during the course of the investigation," the company said in a statement.
Ownership of the OPL 245 block has been in dispute for more than a decade, after former Nigerian oil minister Dan Etete awarded the block for $20 million to Malibu Oil and Gas in 1998.
Etete was a leading shareholder of the company, which only ever paid $2 million for the prospect.
Malibu eventually on-sold the block to Eni and Shell, Reuters reported, with some groups claiming that the joint venture partners used the Nigerian government as a go-between to hide the fact that they were dealing with Etete.
Eni maintained that it dealt exclusively with Shell and the government of Nigeria for the acquisition.
A turbulent 2014
Descalzi replaced Paolo Scaroni as CEO of Eni in May, after the former head was sentenced to three years in prison by an Italian court over inadequate environmental standards at the Enel-operated Porto Tolle power plant during his time at the head of the power utility company.
An attempt by the Italian government to introduce an ethics clause into the oil major's by-laws was shot down by shareholders in the same month, with Scaroni unimpressed by the government's attempts to force managers indicted of certain crimes to leave their positions.