Paula Johnson was born and raised in New York.^[10] She spoke to WGBH about her childhood: "I was very fortunate growing up in Brooklyn. I have one sister, and from a very early age my mother focused on us not only being well-educated, but also thinking independently. I think that gave me the latitude to think differently about my college education. I went to Harvard Radcliffe, which allowed me to really have my first introduction to women's health."^[11] Separately, she said the best piece of advice her mom gave her was to "find your voice and not let failure knock you down."^[12] Additionally, Johnson had always been passionate about science as well as helping others, making a career in medicine ideal.^[13] Johnson resides in Wellesley, Massachusetts with her family. She is married to Robert Sands, a rheumatologist at Atrius Health of Harvard University and has a son who attended Harvard, a teenage daughter,^[13] and two Havanese dogs.^[10]

Johnson's educational career began at Samuel J. Tilden High School in Brooklyn. She then attended Radcliffe College at Harvard University, where she majored in biology and graduated in 1980. Afterward, she attended Harvard Medical School. Developing an interest clinical epidemiology, she also studied at the Harvard School of Public Health. In 1985 she received her medical doctor's degree (M.D.) and a master's in public health (MPH) degrees from Harvard.^[1][7]

After graduating, Johnson began a residency in internal medicine and cardiovascular medicine at Brigham and Women's Hospital, where she decided to specialize in cardiology.^[1] In 1990, she became the first African American ever to hold the position of chief medical resident at the hospital.^[9][1]

Johnson worked in the hospital's cardiac transplant unit and served as director of Quality Management Services. As chief of the Division of Women's Health, she focused on women's access to cardiology care and the quality of that care.^[14] Johnson has also focused much of her work on educating and empowering African-American women, who are 50 percent more likely to die of cardiovascular disease than white women.^[9]

Johnson has been an important voice in making the case that men and women differ at the cellular level. Because of cellular differences, a number of diseases manifest differently in men and women. This has important implications for research, treatment, and patient care. Johnson was the lead author on "Sex-Specific Medical Research: Why Women's Health Can't Wait" (2014), from the Mary Horrigan Connors Center for Women's Health & Gender Biology at Brigham and Women's Hospital.^[15]

"... men and women experience illness differently and this report looks closely at four diseases where this is especially true: cardiovascular disease, lung cancer, depression and Alzheimer's disease. The past two decades have shown not only that sex differences exist, but have produced scientific advancements that enhance our ability to discover why they occur and how we might adapt prevention, detection and treatment strategies for the benefit of women and men alike. Therefore, to ignore these differences challenges the quality and integrity of science and medicine."^[15]

Traditionally, research studies and clinical trials of drugs and other treatments have tested men, not women. The lack of testing on women, combined with sex differences, has meant that women are much more likely to be negatively effected by side effects and differences in response to dosages when drugs are released to market.^{[16][17][18][19][15]} The National Institutes of Health Revitalization Act of 1993 required that women and minorities be represented in any research funded by the NIH.^[20] The resulting twenty years of research have supported the idea that significant sex differences occur in some diseases.^[15]

Johnson argues further that men and women should be tested in separate research trials. Combining data from men and women as if they were a single population may yield results that are applicable to neither sex.^{[16][17][18][19][15]} For example, research has resulted in recommendations that women take doses of the sleeping pill Ambien that are half the dosage recommended for men.^[17] As a result of the work of Johnson and others, the National Institutes of Health (NIH) issued new regulations in 2014, requiring that preclinical research address issues of sex and gender inclusion, to "ensure that the health of the United States is being served by supporting science that meets the highest standards of rigour."^{[16][17][18][19]}

Paula Johnson began working at Wellesley College on July 1, 2016.^[21] In the 2020 fiscal year, Johnson was compensated $585,640 with an additional estimated bonus of $138,371 in her role as College President. Johnson is the third highest paid employee of Wellesley College.^[22]

During the COVID-19 Pandemic in 2020, Paula Johnson joined Massachusetts Governor Baker's 14-member Higher Education Working Group (HEWG) to develop a framework to safely reopen campuses.^[23] In June, she also joined a WBUR digital town hall to analyze how COVID-19 revealed and exacerbated racial inequalities with U.S. Representative Ayanna Pressley and Dr. Mary Travis Bassett.^[24] In 2021, Johnson was nominated to the Governance and Nominating Committee, through the board of directors at Abiomed.^[25] In 2023, Johnson was appointed to the board of directors at Johnson & Johnson.^[26]