We investigated whether a mindfulness meditation program delivered via a smartphone application could improve psychological well-being, reduce job strain, and reduce ambulatory blood pressure during the workday. Participants were 238 healthy employees from two large United Kingdom companies that were randomized to a mindfulness meditation practice app or a wait-list control condition. The app offered 45 prerecorded 10- to 20-min guided audio meditations. Participants were asked to complete one meditation per day. Psychosocial measures and blood pressure throughout one working day were measured at baseline and eight weeks later; a follow-up survey was also emailed to participants 16 weeks after the intervention start. Usage data showed that during the 8-week intervention period, participants randomized to the intervention completed an average of 17 meditation sessions (range 0–45 sessions). The intervention group reported significant improvement in well-being, distress, job strain, and perceptions of workplace social support compared to the control group. In addition, the intervention group had a marginally significant decrease in self-measured workday systolic blood pressure from pre- to post-intervention. Sustained positive effects in the intervention group were found for well-being and job strain at the 16-week follow-up assessment. This trial suggests that short guided mindfulness meditations delivered via smartphone and practiced multiple times per week can improve outcomes related to work stress and well-being, with potentially lasting effects.