Background Electronic health record (EHR) usability and physician task load both contribute to physician professional burnout. The association between perceived EHR usability and workload has not previously been studied at a national level. Better understanding these interactions could give further information as to the drivers of extraneous task load. Objective This study aimed to determine the relationship between physician-perceived EHR usability and workload by specialty and evaluate for associations with professional burnout. Methods A secondary analysis of a cross-sectional survey of US physicians from all specialties was conducted from October 2017 to March 2018. Among the 1250 physicians invited to respond to the subsurvey analyzed here, 848 (67.8%) completed it. EHR usability was assessed with the System Usability Scale (SUS; range: 0-100). Provider task load (PTL) was assessed using the mental demand, physical demand, temporal demand, and effort required subscales of the National Aeronautics and Space Administration Task Load Index (range: 0-400). Burnout was measured using the Maslach Burnout Inventory. Results The mean scores were 46.1 (SD 22.1) for SUS and 262.5 (SD 71.7) for PTL. On multivariable analysis adjusting for age, gender, relationship status, medical specialty, practice setting, hours worked per week, and number of nights on call per week, physician-rated EHR usability was associated with PTL, with each 1-point increase in SUS score (indicating more favorable) associated with a 0.57-point decrease in PTL score (P<.001). On mediation analysis, higher SUS score was associated with lower PTL score, which was associated with lower odds of burnout. Conclusions A strong association was observed between EHR usability and workload among US physicians, with more favorable usability associated with less workload. Both outcomes were associated with the odds of burnout, with task load acting as a mediator between EHR usability and burnout. Improving EHR usability while decreasing task load has the potential to allow practicing physicians more working memory for medical decision making and patient communication.