After completing undergraduate studies in chemistry and mathematics at James Madison University in Harrisonburg, Virginia, Angell spent a year as a Fulbright Scholar studying microbiology in Frankfurt, Germany. After receiving her M.D. from Boston University School of Medicine in 1967, Angell trained in both internal medicine and anatomic pathology and is a board-certified pathologist. She joined the editorial staff of NEJM in 1979, and became executive editor in 1988 and interim editor-in-chief from 1999 until June 2000.

Angell is a frequent contributor to both medical journals and the popular media on a wide range of topics, particularly medical ethics, health policy, the nature of medical evidence, the interface of medicine and the law, and end-of-life healthcare. Her book, Science on Trial: The Clash of Medical Evidence and the Law in the Breast Implant Case (1996) received critical acclaim. With Stanley Robbins and, later, Vinay Kumar, she coauthored the first three editions of the textbook Basic Pathology. She has written chapters in several books dealing with ethical issues in medicine and healthcare.

Angell is a member of the Association of American Physicians, the Institute of Medicine of the National Academy of Sciences, the Alpha Omega Alpha National Honor Medical Society, and is a Master of the American College of Physicians. She is also a fellow of the Committee for the Scientific Investigation of Claims of the Paranormal and is an outspoken critic of medical quackery and the promotion of alternative medicine.

In 1999, Jerome P. Kassirer, M.D., resigned as NEJM's editor-in-chief over a management dispute with the Massachusetts Medical Society, the journal's publisher. NEJM is the oldest medical journal in North America. The dispute was over the Society's plan to use the journal's name to brand and market other sources of healthcare information. Kassirer and Angell were opposed to the plan, because they feared it would lend unearned credibility to health information that has not gone through rigorous peer-review implied by the NEJM label.

The Society denies that this was the reason for the dispute. Angell agreed to serve as interim editor-in-chief until a new editor could be found. She retired from the journal in June 2000 and was replaced by Jeffrey Drazen, M.D. Angell is the only woman to have served as editor-in-chief of the journal since it was founded in 1812.

Although a high-ranking insider of the American medical establishment, Marcia Angell has long spoken frankly of its unhealthy shortcomings. The American healthcare system is in serious crisis, she acknowledged in a PBS special: "If we had set out to design the worst system that we could imagine, we couldn't have imagined one as bad as we have." In the PBS interview, she urges the nation to scrap its failing healthcare system and start over:

Our health care system is based on the premise that health care is a commodity like VCRs or computers and that it should be distributed according to the ability to pay in the same way that consumer goods are. That's not what health care should be. Health care is a need; it's not a commodity, and it should be distributed according to need. If you're very sick, you should have a lot of it. If you're not sick, you shouldn't have a lot of it. But this should be seen as a personal, individual need, not as a commodity to be distributed like other marketplace commodities. That is a fundamental mistake in the way this country, and only this country, looks at health care. And that market ideology is what has made the health care system so dreadful, so bad at what it does.

Angell is a critic of the pharmaceutical industry. With Arnold S. Relman, she argues, "The few drugs that are truly innovative have usually been based on taxpayer-supported research done in nonprofit academic medical centers or at the National Institutes of Health. In fact, many drugs now sold by drug companies were licensed to them by academic medical centers or small biotechnology companies." The pharmaceutical industry estimates that each new drug costs them $800 million to develop and bring to market, but Angell and Relman estimate the cost to them is actually closer to $100 million. Examples are imatinib (Gleevec), zidovudine (AZT) and erythropoietin (Epogen). An unpublished internal NIH study in February 2000 of the 5 top-selling drugs in 1995 (Zantac, Zovirax, Capoten, Vasotec, and Prozac) found that 16 of the 17 key scientific papers leading to the discovery and development came from outside industry.In 2004, she published The Truth About the Drug Companies: How They Deceive Us and What to Do About It.

Angell's position has been challenged by Benjamin Zycher, senior fellow at the pharmaceutical industry-funded Manhattan Institute, who argues that government research can create new drugs, but private industry is needed to produce practical products, by developing mass production methods (for erythropoietin) and versions without limiting adverse effects (for antidepressive drugs).

Marcia Angell is also a critic of the growing acceptance of alternative medicine. In a 1998 NEJM editorial she wrote with Jerome Kassirer, they argued:

It is time for the scientific community to stop giving alternative medicine a free ride... There cannot be two kinds of medicine ... conventional and alternative. There is only medicine that has been adequately tested and medicine that has not, medicine that works and medicine that may or may not work. Once a treatment has been tested rigorously, it no longer matters whether it was considered alternative at the outset. If it is found to be reasonably safe and effective, it will be accepted.

In 1997, Time magazine named Marcia Angell one of the 25 most influential Americans.