The positive-activity model (PAM) proposes how and for whom positive activity interventions work best. This article evaluates the effectiveness of a web-based self-regulation intervention that teaches participants positive activities. Over six weeks, participants engage in different positive activities to meet the particular challenges in flexible work designs (FWD) such as remote work or mobile work. In line with the PAM, we expected the intervention to decrease emotional exhaustion and increase satisfaction with work-life balance via increases in both positive emotions and boundary management. Moreover, individuals’ depressive symptoms were expected to moderate this relationship. In a randomized controlled trial, participants were assigned to a waitlist control group or an intervention group. Study participants received questionnaires before and after the intervention and at a four-week follow-up. The final sample included 288 participants (intervention group: n = 105; control group: n = 183). Results of mixed variance analyses were in line with our predictions. Findings indicate that the intervention is an effective tool for improving well-being and work-life balance for workers with FWD. Changes in positive emotions and boundary management explained intervention effects. The intervention was effective regardless of participants’ baseline level of depressive symptoms.