McCain is the oldest of the four children of John and Cindy Hensley McCain. She has been a public figure for most of her life, appearing at the 1996 Republican National Convention.

She was raised in Phoenix, Arizona and attended Phoenix Country Day School and Xavier College Preparatory, an all-girl Catholic high school. She attended Columbia University, where she earned her bachelor's degree in art history. McCain originally planned to become a music journalist and interned at Newsweek and Saturday Night Live.

McCain says that she is "a woman who despises labels and boxes and stereotypes." McCain has also described herself as a Republican who is "liberal on social issues". She registered as an Independent when she was 18 years old and she voted for John Kerry in the 2004 presidential election. She agrees with her father's positions on global warming and stem-cell research. At first she had doubts about the 2003 invasion of Iraq but subsequently supported her father's position regarding it. She supports same-sex marriage and gay adoption and has stated she is pro-life. McCain objected to the Arizona SB1070 immigration law, which her father supported.

She has commented that the cause of the gay community for equality is "one of the ones closest to my heart". As such, she spoke at the Log Cabin Republicans convention in April 2009. There she encapsulated her cultural and political perspectives with the declaration: "I am concerned about the environment. I love to wear black. I think government is best when it stays out of people's lives and business as much as possible. I love punk rock. I believe in a strong national defense. I have a tattoo. I believe government should always be efficient and accountable. I have lots of gay friends. And yes, I am a Republican." In June 2009, McCain posed for the NOH8 Campaign, a celebrity photo project that protests California's Proposition 8 constitutional amendment banning gay marriage, which her mother Cindy also posed for. She is in favor of repealing Don't Ask, Don't Tell and allowing gays to serve openly in the U.S. military.

In terms of economic policy, she has remarked on The Rachel Maddow Show that "I didn’t even take econ in college. I don’t completely understand it so I’d hate to make a comment one way or the other. That’s — truly of all the things — I keep reading and I just don’t understand it."

On June 12, 2008, McCain wrote on her blog that she had changed her party registration to Republican. She said she did so "as a symbol of my commitment to my dad and to represent the faith I have in his ability to be an effective leader for our country and to grow and strengthen the Republican party when he is elected President of the United States."In her book, "Dirty Sexy Politics," Ms. McCain talks about how she nearly overdosed on Xanax on the day of the elections.

In 2008, she published a book titled My Dad, John McCain. In an interview on Larry King Live in September 2008, McCain stated that she has been too busy to have a romantic relationship while on her father's campaign trail. Although her blogging was devoted towards gaining support for her father among the Generation Z electorate, by October Steve Schmidt and other McCain campaign staffers had banished her into semi-exile on the campaign.

McCain is currently a blogger, and began writing for The Daily Beast in January 2009.

In March 2009, McCain wrote an article for The Daily Beast titled My Beef With Ann Coulter. In this article, she questioned Republican support for journalist Ann Coulter. While Coulter did not respond, conservative radio talk show host Laura Ingraham challenged McCain's article by comparing her to a "Valley Girl." Ingraham also mocked McCain, stating, "Ok, I was really hoping that I was going to get that role in The Real World, but then I realized that, well, they don’t like plus-sized models." McCain responded to Ingraham in a second article for The Daily Beast titled, Quit Talking About My Weight, Laura Ingraham stating, "Instead of intellectually debating our ideological differences about the future of the Republican Party, Ingraham resorted to making fun of my age and weight, in the fashion of the mean girls in high school." McCain also stated on The View that she thought the change in discourse towards her body was "terrible" and further argued: "When Tyra Banks went on her show in a bathing suit and said 'kiss my fat ass,' that's what I feel like. Kiss my fat ass!" Ingraham responded by calling McCain a "useful idiot." During a later interview on Larry King Live, McCain said that as far as she is concerned, "with what's going on with Laura Ingraham, on my end, it's over." She also told King that Coulter never responded to her article, which she stated, "is fine with me. ... All I wanted to do is show women that you don't have to be Ann Coulter and Laura Ingraham to have a place in the Republican Party. ... Supriya Jindal is a good role model, but a lot of people hadn't heard of her."

In April 2009, she inked a six-figure book deal with Hyperion. Some 18,000 people were following her on Twitter. She described her aims in this way: “All I am trying to be is a young, cool Republican woman for other Republican women.” The Politico stated that while John McCain did not emerge from the 2008 election victorious, "his Bud Light-drinking, talk-show-appearing, insouciantly Twittering 24-year-old daughter" did. Speaking at the 2009 Log Cabin Republican Convention, McCain said there was "a war brewing in the Republican Party" between the past and the future, and that "Most of the old school Republicans are scared shitless of that future." She followed that by saying her enjoyment of Twitter was diminished by the presence of top Republican strategist Karl Rove, saying "I can't shake the fact that Karl Rove is following me — it can be creepy" and "We need to take Twitter back from the creepy people."

Statements such as these led news reports and commentators including Rachel Maddow and Kathleen Parker to conclude that McCain had the same "maverick gene" as her father. Following the April 2009 party switch by Senator Arlen Specter from Republican to Democratic, conservative commentator Rush Limbaugh suggested that many Republicans wished both John McCain and Meghan McCain would leave too. Meghan McCain's tweet in response was, "RED TIL I'M DEAD BABY!!! I love the republican party enough to give it constructive criticism, I love my party and sure as hell not leavin!" On a May 2009 episode of the Colbert Report, she stated her support for sex education and criticized Bristol Palin's sexual abstinence campaign, saying it was "not realistic for this generation". McCain also stated her own desires for the Republican Party: "It can be a party for a 24 year-old pro-sex woman. It can be." After John McCain campaign fixture Joe the Plumber made some anti-gay remarks in mid-2009, Meghan McCain took aim at him, saying "Joe the Plumber—you can quote me—is a dumbass. He should stick to plumbing." In September 2009 and February 2010, McCain had repeat stints as guest co-host of The View. In September 2010, McCain appeared on the NPR news quiz show Wait, Wait, Don't Tell Me and won a prize for a listener.

Her campaign memoir, Dirty Sexy Politics, was published in September 2010. In it she finally unleashed her feelings about Palin and described the ups and downs she experienced with the McCain campaign staff; the book also served as a coming-of-age narrative about herself. During the promotional tour for the book, McCain cancelled an appearance at Juniata College due to what she called, "unforeseen professional circumstances." However, according to her Twitter, she was actually in Las Vegas on a break.