Burnout is common among physicians and is associated with suboptimal patient outcomes. Little is known about how experiences with patients, families, and visitors differ by physician characteristics or contribute to the risk of burnout. To examine the occurrence of mistreatment and discrimination by patients, families, and visitors by physician characteristics and the association between such interactions and experiencing burnout. This cross-sectional survey was conducted from November 20, 2020, to March 23, 2021, among US physicians. Mistreatment and discrimination were measured using items adapted from the Association of American Medical College's Graduation Questionnaire with an additional item querying respondents about refusal of care because of the physicians' personal attributes; higher score indicated greater exposure to mistreatment and discrimination. Burnout as measured by the Maslach Burnout Inventory. Of 6512 responding physicians, 2450 (39.4%) were female, and 369 (7.2%) were Hispanic; 681 (13.3%) were non-Hispanic Asian, Native Hawaiian, or Pacific Islander; and 3633 (70.5%) were non-Hispanic White individuals. Being subjected to racially or ethnically offensive remarks (1849 [29.4%]), offensive sexist remarks (1810 [28.7%]), or unwanted sexual advances (1291 [20.5%]) by patients, families, or visitors at least once in the previous year were common experiences. Approximately 1 in 5 physicians (1359 [21.6%]) had experienced a patient or their family refusing to allow them to provide care because of the physician's personal attributes at least once in the previous year. On multivariable analyses, female physicians (OR, 2.33; 95% CI, 2.02-2.69) and ethnic and racial minority physicians (eg, Black or African American: OR, 1.59; 95% CI, 1.13-2.23) were more likely to report mistreatment or discrimination in the previous year. Experience of mistreatment or discrimination was independently associated with higher odds of burnout (vs score of 0 [no mistreatment], score of 1: OR, 1.27; 95% CI, 1.04-1.55; score of 2: OR, 1.70; 95% CI, 1.38-2.08; score of 3: OR, 2.20; 95% CI, 1.89-2.57). There was no difference in the odds of burnout by gender after controlling for experiencing mistreatment and discrimination score and other demographic factors, specialty, practice setting, work hours, and frequency of overnight call. In this study, mistreatment and discrimination by patients, families, and visitors were common, especially for female and racial and ethnic minority physicians, and associated with burnout. Efforts to mitigate physician burnout should include attention to patient and visitor conduct.