The efficacy of providing self-acupressure educational materials in reducing stress and improving health-related quality of life (HRQOL) is uncertain. Evidence-based data to recommend for or against self-acupressure as an intervention for reducing stress and improving HRQOL is needed. The Self-Acupressure for Stress (SAS) trial evaluates whether providing self-acupressure educational materials would reduce stress and improve HRQOL among health care providers (HCPs). Randomized behavioral clinical trial. The entire study took place remotely. One hundred fifty-nine adult HCPs with no prior experience or training in acupressure. The intervention group received self-acupressure educational materials. Primary outcomes were perception of stress measured by the Perceived Stress Scale (PSS), as well as scores on the physical and mental components of the 12-item Short Form Health Survey version 2 (SF-12v2). From the baseline to midpoint evaluations, the intervention group significantly reduced their PSS score (P ≤ .001) and increased their SF-12v2 Mental score (P = .002) but not their SF-12v2 Physical score (P = .55). These findings persisted at the final follow-up (both PSS and SF-12v2 Mental changes from baseline P < .001). However, the control group also significantly improved their SF-12v2 Mental from baseline to midpoint (P = .01) which was maintained at final follow-up (P = .02), whereas PSS and SF-12v2 Physical did not significantly change from baseline at either mid or final. Finally, the intervention group improved by significantly more than the control group from baseline to final follow-up for both PSS (P = .007) and SF-12v2 Mental (P = .02) HRQOL measures. The trial was not blinded. Among HCPs during the coronavirus disease 2019 (COVID-19) pandemic, the provision of self-acupressure educational materials safely improved self-reported assessments of perception of stress and mental health. Self-acupressure represents a promising intervention for other populations. The study findings support the use of self-acupressure to reduce stress and improve HRQOL. ClinicalTrials.gov: NCT04472559.