Background: Stress management in the workplace is essential for a healthy mental and physical state. Due to technological advancements, individually tailored therapy and online cognitive behavioral therapy (CBT) are on the rise. Objective: This study analyzed the efficacy of a smartphone app based on third-wave CBT tailored to an individual. Methods: A randomized controlled trial was conducted with 126 participants who were divided into 2 groups. The intervention group used the smartphone app BetterLife for 10 weeks, while the control group was placed on a waiting list for the same duration. The Perceived Stress Scale-10 (PSS), Korean Utrecht Work Engagement Scale-9 (UWES), World Health Organization Quality of Life Assessment (WHOQOL), Beck Depression Inventory-II (BDI), and Beck Anxiety Inventory (BAI) were administered at baseline and after 10 weeks to both groups. Results: Of the 126 participants, 11 dropped out during the trial. A 2-way repeated measure analysis of covariance was conducted, controlling for baseline BDI. There were greater improvements in PSS (F=24.33, P<.001,eta(2)=0.17) and UWESK scores (F=8.32, P=.0046, eta(2)=0.06) in the intervention group than in the control group. WHOQOL scores exhibited statistically significant improvement in the intervention group in the overall quality of life (F=8.19, P=.0049,eta(2)=0.06), physical health (F=8.87, P=.003, eta(2)=0.07), psychological health (F=13.32, P<.001,eta(2)=0.10), social relationships (F=19.43, P<.001,eta(2)=0.14), and environmental domains (F=10.14, P=.002, eta(2)=0.08) but not overall health (F=1.68, P=.20). BDI (F=7.17, P=.008, eta(2)=0.06) and BAI (F=6.00, P=.02, eta(2)=0.05) showed a statistically significant improvement in the intervention group, but this significance did not survive the Bonferroni correction (P<.005). Conclusions: These results provide evidence that smartphone-based CBT is a viable option for reducing stress in the workplace.