Gawande was born in Brooklyn, New York to Indian Maharashtrian immigrants to the United States, both doctors. The family soon moved to Athens, Ohio, where Gawande and his sister grew up. He obtained an undergraduate degree from Stanford University in 1987, was a Rhodes scholar (earning a degree in Philosophy, Politics & Economics from Balliol College, Oxford in 1989), and later graduated from Harvard Medical School. He also has a Master of Public Health degree from the Harvard School of Public Health.

As a student Gawande was a volunteer for Gary Hart's campaign. As a Rhodes Scholar, he spent one year at Oxford University. After graduation, he joined Al Gore's 1988 presidential campaign. He worked as a health-care researcher for Congressman Jim Cooper (D-TN), who was author of a "managed competition" health care proposal for the Conservative Democratic Forum. After two years he left medical school to become Bill Clinton's health care lieutenant during the 1992 campaign and became a senior adviser in the Department of Health and Human Services after Clinton's inauguration. He directed one of the three committees of the Clinton Health Care Task Force, supervising 75 people and defined the benefits packages for Americans and subsidies and requirements for employers. He returned to medical school in 1993 and earned his M.D in 1995. Former Policymaker Opts for Hands-On Health Care - International Herald Tribune

Soon after he began his residency, his friend Jacob Weisberg, editor of Slate, asked him to contribute to the online magazine. His pieces on the life of a surgical resident caught the eye of the New Yorker which published several pieces by him before making him a staff writer in 1998.

A June 2009 New Yorker essay by Gawande, "The Cost Conundrum", which used as an example the town of McAllen, Texas to argue that unnecessary medical tests and procedures were a primary factor in driving up the cost of health care in the U.S., was cited by President Barack Obama during Obama's attempt to get health care reform legislation passed by the United States Congress. According to Senator Ron Wyden, the article "affected [Obama's] thinking dramatically", and soon after its publication, Obama showed the article to a group of senators including Wyden and said, "This is what we’ve got to fix." Gawande, in turn, later expressed approval for Obama's health care proposals on the New Yorker "News Desk" blog. After reading the New Yorker article, Warren Buffett's long-time business partner Charlie Munger mailed a check to Gawande in the amount of $20,000 as a thank you to Dr. Gawande for providing something so socially useful. Gawande reportedly donated the $20,000 to the Brigham and Women's Hospital Center for Surgery and Public Health.

In addition to his popular writing, Gawande has published studies on topics including military surgery techniques and error in medicine, included in the New England Journal of Medicine. He is also the director of the World Health Organization's Global Patient Safety Challenge. His essays have appeared in The Best American Essays 2003, "The Best American Science Writing 2002, and The Best American Science Writing 2009.

Gawande published his first book, Complications: A Surgeon's Notes on an Imperfect Science, in 2002. It was a National Book Award finalist, and has been published in over one hundred countries.

His second book, Better: A Surgeon's Notes on Performance, was released in April 2007. It discusses three virtues that Gawande considers to be most important for success in medicine: diligence, doing right, and ingenuity. Gawande offers examples in the book of people who have embodied these virtues. The book strives to present multiple sides of contentious medical issues, such as malpractice law in the US, physicians' role in capital punishment, and treatment variation between hospitals.

Gawande released his third book, The Checklist Manifesto: How to Get Things Right, in 2009. It discusses the importance of organization and pre-planning (such as through checklists) in both medicine and the larger world. The Checklist Manifesto reached the New York Times Hardcover nonfiction bestseller list in 2010.

In 2006 he was named a MacArthur fellow for his work investigating and articulating modern surgical practices and medical ethics.,

In the medical field, he is an expert on the removal of cancerous endocrine glands. He was also named one of the 20 Most Influential South Asians by Newsweek in 2004.

In the 2010 Time 100 he was included (fifth place) in Thinkers Category.

Gawande lives in Newton, Massachusetts with his wife, Kathleen Hobson, and his three children (Walker, Hattie and Hunter).