ImportanceDuring the COVID-19 pandemic, health care workers (HCWs) reported a significant decline in their mental health. One potential health behavior intervention that has been shown to be effective for improving mental health is exercise, which may be facilitated by taking advantage of mobile application (app) technologies.ObjectiveTo determine the extent to which a 12-week app-based exercise intervention can reduce depressive symptoms, burnout, and absenteeism in HCWs, compared with a wait list control condition.Design, Setting, and ParticipantsA 2-group randomized clinical trial was conducted, with participants screened from April 6 to July 4, 2022. Participants were recruited from an urban health care organization in British Columbia, Canada. Participants completed measures before randomization and every 2 weeks thereafter.InterventionsExercise condition participants were asked to complete four 20-minute sessions per week using a suite of body weight interval training, yoga, barre, and running apps. Wait-listed control participants received the apps at the end of the trial.Main Outcomes and MeasuresThe primary outcome consisted of the between-group difference in depressive symptoms measured with the 10-item Center for Epidemiological Studies Depression Scale. The secondary outcomes corresponded to 3 subfacets of burnout (cynicism, emotional exhaustion, and professional efficacy) and absenteeism. Intention-to-treat analyses were completed with multilevel structural equation modeling, and Feingold effect sizes (ES) were estimated every 2 weeks.ResultsA total of 288 participants (mean [SD] age, 41.0 [10.8] years; 246 [85.4%] women) were randomized to either exercise (n = 142) or wait list control (n = 146) conditions. Results revealed that ESs for depressive symptoms were in the small to medium range by trial’s end (week 12, −0.41 [95% CI, −0.69 to −0.13]). Significant and consistent treatment effects were revealed for 2 facets of burnout, namely cynicism (week 12 ES, −0.33 [95% CI, −0.53 to −0.13]) and emotional exhaustion (week 12 ES, −0.39 [95% CI, −0.64 to −0.14]), as well as absenteeism (r = 0.15 [95% CI, 0.03-0.26]). Adherence to the 80 minutes per week of exercise decreased from 78 (54.9%) to 33 (23.2%) participants between weeks 2 and 12.Conclusions and RelevanceAlthough exercise was able to reduce depressive symptoms among HCWs, adherence was low toward the end of the trial. Optimizing adherence to exercise programming represents an important challenge to help maintain improvements in mental health among HCWs.Trial RegistrationClinicalTrials.gov Identifier: NCT05271006