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President Antonio Neri will take on the role of CEO as of Feb. 1, 2018, and both Whitman and Neri will be on the board, the company announced Tuesday.
HPE shares fell more than 6 percent after hours. The company also reported quarterly earnings on Tuesday.
"Today, Hewlett Packard moves forward as four industry-leading companies that are each well positioned to win in their respective markets," Whitman said in a statement. "Now is the right time for Antonio and a new generation of leaders to take the reins of HPE. I have tremendous confidence that they will continue to build a great company that will thrive well into the future."
Whitman will exit a much different company than the one she joined in 2011. Whitman restructured Hewlett-Packard into two brands, spinning off other businesses and streamlining HPE to keep up with cloud-savvy competitors. Whitman's departure comes after she was considered for, but ultimately didn't take, a job as the CEO of ride-hailing giant Uber.
HPE was formed in late 2015 as a result of the split of HP into two companies. At that time, Whitman went from CEO of the larger legacy company to CEO of HPE, while Dion Weisler went from executive vice president of the old HP's printing and personal systems group to CEO of HP Inc.
Whitman made her name in business as the CEO of eBay, which became an e-commerce giant under her leadership. Whitman, an Uber investor, helped Uber amid a shaky executive transition earlier this year, and briefly flirted with a slot as CEO.
Even if she was offered the job, Whitman told CNBC in September that she wasn't sure she would have taken it. But leaks of her discussions with Uber became a topic of discussion among Wall Street analysts and investors during a September earnings call.
"I might be the only CEO in America who likes running something smaller than something bigger, because it gives me a chance to be in-depth with customers," Whitman said. "I like a more nimble, agile company and I have no plans to leave HPE. ... It's hard to imagine another five [years] but listen, I am here for the foreseeable future, because there's still work to do."
Whitman, a former California gubernatorial candidate, said in a statement that she did not plan on seeking elected office: "I stay active in politics by contributing to candidates from both sides of the aisle who I agree with on core issues, but aside from that, I have no plans to get involved directly."
On a conference call with analysts, Whitman said she's taking a little down time, and there's "no chance" she will join a competitor to HPE or HP.
Neri has been with the company since 1995, working his way up to the company's top ranks.
"HPE is in a tremendous position to win, and we remain focused on executing our strategy, driving our innovation agenda, and delivering the next wave of shareholder value," he said in a statement.
HPE also reported quarterly earnings on Tuesday. The company posted adjusted earnings of 31 cents per share on revenue of $7.87 billion for the fiscal fourth quarter. That's above analyst expectations of 28 cents per share on revenue of more than $7.7 billion, according to a Thomson Reuters consensus estimate. Revenue in the year-earlier period was $7.32 billion.
The company also reported an outlook for the next fiscal year that was in line with expectations. HPE expects diluted earnings per share of $1.15 to $1.25 on an adjusted basis. Analysts polled by Thomson Reuters expected a midpoint of $1.20 for the 2018 fiscal year.
— Meg Whitman will appear on CNBC's "Squawk on the Street " on Wednesday in an exclusive interview.