Background: Research investigating the potential for digital mental health interventions with integrated relational agents to improve mental health outcomes is in its infancy. By delivering evidence-based mental health interventions through tailored, empathic conversations, relational agents have the potential to help individuals manage their stress and mood, and increase positive mental health. Aims: The aims of this study were twofold: 1) to assess whether a smartphone app delivering mental health support through a relational agent, Woebot, is associated with changes in stress, burnout, and resilience over 8 weeks, and 2) to identify demographic and clinical factors associated with changes in these outcomes. Method: This exploratory, non-randomized, single-armed, open-labeled trial was conducted from May to July 2022. A total of 256 adults (mean age 39 ± 13.35; 72 % females) recruited through social media advertising enrolled in the study. Participants completed an 8-week intervention period during which they were invited to use a smartphone app called Woebot-LIFE that delivers cognitive behavioral therapy through a relational agent called "Woebot". Participant-reported measures of stress, burnout, and resilience were collected at Baseline, and Week 8. Changes in these outcomes during the study period were assessed. Bivariate and stepwise multiple regression modeling was used to identify sociodemographic and clinical factors associated with observed changes over the 8-week study period. Results: Exposure to Woebot-LIFE was associated with significant reductions in perceived stress and burnout and significantly increased resilience over the 8-week study period. A greater reduction in stress was observed among those with clinically elevated mood symptoms (i.e., Patient Health Questionnaire-8 or Generalized Anxiety Disorder 7-item scores ≥10) at baseline compared to those without; however, the differences in the improvements in resilience scores and burnout between the two groups were not statistically significant. Although a difference in the magnitude of change in stress was observed for participants with and without clinically elevated mood symptoms at baseline, significant improvements in stress, burnout, and resilience over the 8-week study period were observed for both groups. Bivariate analyses showed that race, insurance type, and baseline level of resilience were associated with changes in each of the outcomes, though baseline resilience was the only factor that remained significantly associated with changes in the outcomes in the stepwise multiple regression analyses. Conclusion: Results of this single-arm, exploratory study suggest that conversational agent-guided mental health interventions such as Woebot-LIFE may be associated with reduced stress and burnout and increased resilience in both clinical and non-clinical populations.