Malkin was born in Philadelphia, Pennsylvania as the first of two children to Philippine citizens Apolo DeCastro Maglalang, a physician-in-training, and Rafaela (née Perez), a homemaker and schoolteacher. Her parents had arrived in the United States earlier that year on an employer-sponsored visa.

After her father finished his medical training, the family moved to the small southern New Jersey town of Absecon, where she and her younger brother were raised in the Catholic faith. She has described her parents as Reagan Republicans who were "not incredibly politically active”.

Malkin has spoken of a formative event when she was in kindergarten: one day, the other children called her a racist name, and she went home crying. Her mother comforted her and told her that, "everyone has prejudice." She has said that she is "eternally grateful" for that counsel. Malkin graduated from Holy Spirit Roman Catholic High School in 1988, where she edited the school newspaper and planned to become a concert pianist.

Malkin originally planned to pursue a bachelor's degree in music at Oberlin College, but changed her major to English. At Oberlin, she began writing for an independent newspaper that was being started by Jesse Dylan Malkin, a Rhodes Scholar with established conservative leanings; the two eventually began dating. Malkin's first article attacked Oberlin's affirmative-action program, which received a "hugely negative response" from other students on campus. In June 1992, Malkin graduated from Oberlin College. She later described her alma mater as a "radically left-wing, liberal arts college".

On July 23, 1993, Michelle and Jesse married. Eventually, Jesse worked as an associate policy analyst and economist focusing on healthcare issues for the Rand Corporation. In 2004, Malkin reported on her website that her husband had left his "lucrative health-care consulting job" to be a stay-at-home dad, raising their daughter Veronica Mae (born 1999) and son Julian Daniel (born 2003).

As of September 2009, Malkin and her family reside in Colorado Springs, Colorado.

Malkin began her journalism career at the Los Angeles Daily News, working as a columnist from 1992 to 1994. In 1995, she worked in Washington, D.C., as a journalism fellow at the Competitive Enterprise Institute, a libertarian think tank which is dedicated to the promotion of free enterprise without government regulation. In 1996, she moved to Seattle, Washington, where she wrote columns for The Seattle Times. Malkin became a nationally-syndicated columnist with Creators Syndicate in 1999.

For many years, Malkin was a frequent commentator for Fox News Channel and a regular guest host of The O'Reilly Factor. In 2007, she announced that she would not return to The O'Reilly Factor, claiming that Fox News had mishandled a dispute over derogatory statements made about her by Geraldo Rivera in a Boston Globe interview.[NB 1] Since 2007, she has concentrated on her writing, blogging and public speaking, although she still appears on television occasionally, especially with Sean Hannity on Fox News and Fox & Friends once a week. In December 2009, Malkin began writing for the St. Louis Globe-Democrat.

In August 2004, following claims by Swift Boat Veterans for Truth that presidential candidate John Kerry had exaggerated his record during the Vietnam War, Malkin appeared on MSNBC's Hardball with Chris Matthews and stated that there were "legitimate questions" over whether Kerry's wounds were "self-inflicted." When host Chris Matthews pressed her eleven times over his interpretation of 'self-inflicted' to imply that Kerry had shot himself on purpose, she said that other soldiers had made this claim, referring to other injuries. Matthews said "No irresponsible comments are going to be made on this show"; Malkin criticized Matthews and the MSNBC staff in her blog the following day. Georgia Senator Zell Miller accused Matthews of "browbeating" Malkin.

Her first book, Invasion: How America Still Welcomes Terrorists, Criminals, and Other Foreign Menaces, was published in 2002 and was a New York Times bestseller.