Objectives <p>This study examined whether adding non-mindfulness practices (based on positive psychology and cognitive–behavioral therapy) and human support to mindfulness-based interventions (MBIs) improved their effectiveness in treating depression and enhancing mental well-being and mindfulness.</p> Method <p>Participants experiencing emotional distress (<i>n</i> = 375) were randomly assigned to waitlist control, mindfulness alone (MA), multicomponent MBI without human support (MM; incorporating non-mindfulness practices in addition to MA), and multicomponent MBI with human support (MM-H) groups. Self-help interventions were delivered online over 25 days, with assessments conducted at preintervention, postintervention, and at 1-month and 3-month follow-ups.</p> Results <p>Compared with the waitlist control, all interventions improved depression and nonreacting (i.e., nonreactivity to inner experience), with small to medium effect sizes. However, intervention effects on mental well-being, observing, describing, acting with awareness, and nonjudging were non-significant. Depression reductions were sustained in the MM and MM-H groups but not in the MA group at the 3-month follow-up. No significant differences emerged between intervention groups on any outcome. Nonreacting mediated the effects of all three interventions on depression. Observing mediated improvements in mental well-being for the MM and MM-H groups but not for the MA group.</p> Conclusions <p>Brief digital MBIs can effectively reduce depression, with nonreacting as a key mediator. The mediating role of observing in well-being may depend on intervention components. Combining mindfulness, non-mindfulness practices, and human support may enhance long-term effects on depression. Targeting nonreacting and observing in MBIs may facilitate improvements in depression and well-being, respectively.</p> Preregistration <p>This study is not preregistered.</p>