Matthews attended La Salle College High School. Matthews is a 1967 graduate of the College of the Holy Cross in Worcester, Massachusetts, and did graduate work in Economics at the University of North Carolina at Chapel Hill. Matthews was also a visiting fellow at Harvard University's Institute of Politics.

Matthews served in the United States Peace Corps in Swaziland from 1968 to 1970 as a trade development adviser.

When Matthews first arrived in Washington, D.C., he worked as an officer with the United States Capitol Police. Subsequently, Matthews served on the staffs of four Democratic Members of Congress, including Senators Frank Moss and Edmund Muskie. In 1974, Matthews mounted an unsuccessful campaign for Pennsylvania's 4th congressional district seat in the U.S. House of Representatives in which he received about 24% of the vote in the primary. Matthews was a presidential speechwriter during the Carter Administration, and later worked for six years as Chief of Staff to longtime Speaker of the House of Representatives Tip O'Neill, playing a direct role in many key political battles with the Reagan Administration.

Matthews has been married since 1980 to Kathleen Matthews, who anchored News 7 on WJLA-TV, the ABC affiliate in Washington, D.C., before accepting a position as an executive vice President with Marriott International. The couple have three children: Michael, Thomas, and Caroline. His brother Jim Matthews, a Republican, is a former county commissioner in Montgomery County, Pennsylvania.

Matthews worked in print media for 15 years, spending 13 years as Washington, D.C. bureau chief for the San Francisco Examiner (1987–2000) and two years as a nationally syndicated columnist for the San Francisco Chronicle. Matthews covered the fall of the Berlin Wall, the first all-races election in South Africa, and the Good Friday Peace Talks in Northern Ireland. In 1997 and 1998, his research in the National Archives produced a series of exclusives on the Nixon presidential tapes. Matthews has covered American presidential election campaigns since 1988.

In 1997, Matthews began his own weeknight talk show, Hardball with Chris Matthews, which originally aired on America's Talking but is currently on MSNBC. Hardball features pundits and elected officials as guests.

Matthews has said, "I'm more conservative than people think I am.... I voted for George W. in 2000." Salon.com has called him the "most conservative voice" on MSNBC's primetime lineup. Matthews has been accused by Media Matters for America of having panels of guests that skew to the right and of supporting Republicans in his own questions and comments.

The Chris Matthews Show aired in syndication from 2002 until 2013. The show was formatted as a political roundtable consisting of four journalists and Matthews, who served as the moderator. He is estimated to earn more than $5 million a year. He is the author of eight best-selling books:

In 2004, at the Democratic National Convention, Matthews predicted that he had "just seen the first black president".

Matthews is the recipient of several awards, including The Pennsylvania Society's Gold Medal for Distinguished Achievement in 2005, the Abraham Lincoln Award from the Union League of Philadelphia, the David Brinkley Award for Excellence in Broadcast Journalism, the John F. Kennedy Memorial Award, and the 2016 Tip O'Neill Irish Diaspora Award.

The Huffington Post reported on Matthews' emotional expressions of support for Barack Obama during the 2008 Presidential election, quoting him as saying "I have to tell you, you know, it’s part of reporting this case, this election, the feeling most people get when they hear Barack Obama’s speech. My, I felt this thrill going up my leg. I mean, I don’t have that too often."

In 2002, Matthews was hospitalized with malaria, which he evidently contracted on one of his visits that year to Africa. He has also had other health problems, including diabetes (which he acknowledged having on the Hardball broadcast of December 7, 2009) and pneumonia.

Elusive Hero spent 12 weeks on The New York Times' bestseller list. The book was lauded by critics. "Matthews excels in capturing the tribalism of the Irish Catholic culture and experience Kennedy both absorbed and overcame as he made his way...[and] is at his best in describing political dynamics," The Washington Post said. "Matthews proves a compelling storyteller," said The Boston Globe. "Matthews has produced a valuable addition to the literature about the life and career of our 35th President," said The Christian Science Monitor. "Matthews's stirring biography reveals Kennedy as a 'fighting Prince never free from pain, never far from trouble, and never accepting the world he found,'" said Publishers Weekly.

In 2013, Matthews announced that he had signed a long-term contract extension with MSNBC but that he would no longer host The Chris Matthews Show in order to focus his efforts on Hardball, writing books, and producing documentaries. The final episode of The Chris Matthews Show aired on July 21.

Matthews was the commencement speaker at Ohio State University on May 4, 2014, and at the University of Rochester on May 18, 2014, where he was awarded an honorary Doctor of Letters.

In December 2017, several news outlets reported that in 1999, Matthews was accused by a female assistant Producer on his program for making inappropriate jokes and comments. He was formally reprimanded by his employer CNBC and his accuser was awarded a $40,000 separation package settlement.