Whitman attended Cold Spring Harbor High School in Cold Spring Harbor, New York, graduating after three years in 1974. In her memoirs, she says she was in the top 10 of her class. She wanted to be a Doctor, so she studied math and science at Princeton University. However, after spending a summer selling advertisements for a magazine, she changed over to the study of economics, earning a B.A. with honors in 1977. Whitman then obtained an M.B.A. from Harvard Business School in 1979.

Beginning her career in 1979 as a brand manager at Procter & Gamble in Cincinnati, Ohio. Whitman later moved on to work as a consultant at Bain & Company's San Francisco office. She then rose through the ranks to achieve the position of senior vice President.

A native of Cold Spring Harbor, a hamlet of Huntington, New York, Whitman is a graduate of Princeton University and Harvard Business School. Whitman served as an executive in The Walt Disney Company, where she was Vice President of Strategic Planning throughout the 1980s. In the 1990s, she served as an executive for DreamWorks, Procter & Gamble, and Hasbro.

Whitman became vice President of strategic planning at The Walt Disney Company in 1989. Two years later she joined the Stride Rite Corporation, before becoming President and CEO of Florists' Transworld Delivery in 1995.

As Hasbro's Playskool Division General Manager, she oversaw global management and marketing of two children's brands, Playskool and Mr. Potato Head starting in January 1997. She also imported the UK's children's television show Teletubbies into the U.S.

Whitman joined eBay on March 1998, when it had 30 employees and revenues of approximately $4 million. During her time as CEO, the company grew to approximately 15,000 employees and $8 billion in annual revenue by 2008. Originally, when Whitman had joined eBay, she found the website as a simple black and white webpage with courier font. On her first day, the site crashed for eight hours. She believed the site to be confusing and began by building a new executive team. Whitman organized the company by splitting it into twenty-three Business categories. She then assigned executives to each, including some 35,000 subcategories. In 2004, Whitman made several key changes in her management team. Jeff Jordan took over PayPal, Matt Bannick took control of international operations and Bill Cobb was placed in control of U.S. operations, which has the colorful U.S. logo, while each international site has unique branding.

Whitman has made monetary donations to various candidates and political action committees (PAC). While these have gone to both Republicans and Democrats, the donations are weighted to Republicans. Though Whitman has contributed to a few Democrats, including Senator Barbara Boxer; donating $4,000 to her campaign and serving on the "Friends of Boxer" committee in 2004, she donated more than $225,000.00 during the same period to Republicans, eBay's PAC and to Americans for a Republican Majority, the PAC of former Representative Tom DeLay.

During Whitman's tenure as CEO, eBay completed the purchase of Skype for $4.1B in cash and stock in September 2005. eBay later admitted that it had overpaid and, in 2009, eBay sold Skype to a group of Investors led by Silver Lake Partners at a valuation of $2.75B. In 2011, after the first papers were filed for a possible IPO, Microsoft purchased Skype for US$8.5B.

Whitman said that if elected, on her first day she would have suspended AB 32, the Global Warming Solutions Act of 2006, for a year to study its potential economic implications. AB 32 requires the state to cut greenhouse gas emissions by 30 percent by 2020. At the state Republican Convention in March 2010, Whitman described California Republican Governor Arnold Schwarzenegger's climate change bill as a "job-killer". Whitman opposed Proposition 23, which would delay the global warming law AB 32 until California's unemployment falls to 5.5 percent and stays there for a year, stating that the proposition did not reasonably balance the need to protect jobs with the need to preserve environment.

Whitman resigned as CEO of eBay in November 2007, but remained on the board and served as an advisor to new CEO John Donahoe until late 2008. She was inducted into the U.S. Business Hall of Fame in 2008. "I've said for some time that 10 years is roughly the right time to stay at the helm at a company like ours", she said in an interview with the San Francisco Chronicle, adding that "it's time for new leadership, a new perspective and a new vision."

Whitman was a supporter of former Massachusetts Governor Mitt Romney's presidential campaign in 2008 and was on his national Finance team. She was also listed as Finance co-chair of Romney's exploratory committee. After Romney stepped out of the race and endorsed John McCain, Whitman joined McCain's presidential campaign as a national co-chair. McCain mentioned Whitman as a possible Secretary of the Treasury during the second presidential debate in 2008, but lost the election to Barack Obama.

She stated that illegal immigrant students should be prohibited from attending state-funded institutions of higher education. Currently, California state law permits this. In 2009, Whitman called for "a path to legalization" of illegal immigrants. In a 2010 interview on television station KTLA, Whitman said, "I want to hold employers accountable for hiring only documented workers." Whitman came under fire for hiring an illegal immigrant herself (see "Housekeeper Controversy" above).

In September 2010, Nicky Diaz Santillan revealed that she was employed in the Whitman household as a housekeeper and nanny from 2000–2009 despite her status as an illegal worker. Whitman's campaign released documents which she says Santillan provided prior to her employment including a driver's license, social security ID, and application. Santillan says Whitman knew she was undocumented, producing a 2003 letter from the Social Security Administration stating that her Social Security number did not match her name. Whitman initially stated that they "never received those letters", however, after a hand-written note on the document was shown, believed to be from Whitman's husband, they acknowledged they may have received it, but forgot. Santillan's attorney, Gloria Allred, states that Santillan was fired for the sake of the campaign. Whitman's campaign maintains that this is a political attack, stating that Allred is a Jerry Brown supporter. Brown, Allred and Santillan all deny this. Crystal Williams, Director of the American Immigration Lawyers Association stated "Not only is accepting the documents all the law required [Whitman] to do, but there's a counterbalancing anti-discrimination law that keeps her from probing further or demanding different documents." Others disagree; immigration Lawyer Greg Siskind states Whitman was the employer, and the documents by law needed to be signed by her but were not, nor did they have a social security number on them; the Fort Worth Star-Telegram noted that Whitman "hired her, paid her and had direct contact with her for nine years", so should have known her legal status. The Los Angeles Times noted that Latino voters were more likely interested that Whitman treated Santillan "like a piece of garbage" when the maid asked for help finding an immigration attorney, and Whitman allegedly stated "you don't know me and I don't know you".

In January 2011, Whitman joined Hewlett-Packard's (HP) board of Directors. She was named CEO on September 22, 2011. As well as renewing focus on HP’s Research & Development division, Whitman’s major decision during her first year as CEO has been to retain and recommit the firm to the PC Business that her predecessor announced he was considering discarding.

During the 2012 Republican primaries, Whitman endorsed Mitt Romney, who praised her. Whitman's name was mentioned as a possible cabinet member in a Romney administration before he lost to Obama.

During the 2010 California gubernatorial election, Whitman supported California's Proposition 8, which reversed In re Marriage Cases and defined marriage as a union between one man and one woman in the state. Whitman also criticized Governor Arnold Schwarzenegger and Attorney General Jerry Brown for not defending Proposition 8 in the federal judicial system. However, on February 26, 2013, Whitman confirmed that she had reversed that opinion. Whitman stated, "At the time, I believed the people of California had weighed in on this question and that overturning the will of the people was the wrong approach," and "The facts and arguments presented during the legal process since then have had a profound impact on my thinking." Whitman also believes that gay and lesbian couples should be permitted to adopt children. Whitman supports abortion rights.

During the 2016 Republican primaries, Whitman was Finance co-chair of Chris Christie's presidential campaign. After Christie withdrew from the race and subsequently endorsed Donald Trump, Whitman criticized it as "an astonishing display of political opportunism" and called on other Christie donors to reject Trump, whom she compared to Adolf Hitler and Benito Mussolini. In August, Whitman endorsed Democrat Hillary Clinton's presidential campaign, stating that to vote for Trump "out of party loyalty alone would be to endorse a candidacy that I believe has exploited anger, grievance, xenophobia and racial division". Acknowledging policy differences with Clinton, Whitman nonetheless praised her "temperament, global experience and commitment to America’s bedrock national values". She called on all Republicans "to put country first before party" and added that she would support the campaign financially.

On November 21, 2017 it was announced Whitman was stepping aside as the CEO of HPE effectively February 1, 2018 with HPE President Antonio Neri taking over as CEO.

Goldman Sachs, whose executives donated $100,000 to the Whitman campaign, manages a part of Whitman's fortune. As CEO of eBay, Whitman earned approximately $1.78 million resulting from a practice known as spinning whereby executives who did Business with Goldman Sachs could reap profits by getting early deals before the public on hot IPOs offered by the bank. Whitman later resigned from the Goldman Sachs board after some expressed concern over her receiving shares from Goldman Sachs. In commenting on Whitman’s resignation from the Goldman Sachs board, eBay spokesman Henry Gomez told The Wall Street Journal at the time that, "If we wanted to use Goldman's services, she doesn't want there to be even the slightest perception of any conflict. She's doing this because she thinks quite highly of the firm." While Whitman was on Goldman Sachs' board, she served on the compensation committee, which approved multimillion-dollar bonus packages for then-CEO Henry Paulson and his top aides. Public domain documents reveal that Whitman has a multimillion-dollar stake in 21 investment funds managed by Goldman Sachs. Given Goldman Sachs' major Investments in California state finances, all these ties to Goldman Sachs led to considerable controversy during the gubernatorial campaign. In response, Whitman vowed to eliminate any potential conflicts of interest, and publicly stated that she would immediately sell her Goldman Sachs stock and put her Goldman Sachs-managed Investments in a blind trust if elected governor.