Preventing and reducing depression in first-year college students are crucial areas in need of attention and resources. Programs that are cost-effective and time-efficient, that have replicable benefits across samples, are sorely needed. This study aims to examine whether a previously studied acceptance-based behavioral (ABBT) program, the Mindful Way Through the Semester (MWTS), is effective in comparison to a control condition at decreasing levels of depression and enhancing acceptance and academic values when integrated into a first-year undergraduate experience course. The current study also sought to examine the association between change in acceptance, mindfulness practice, and values practice on outcomes. Two hundred thirteen students were assigned to either the MWTS workshop condition or the control condition (in which the first-year experience curriculum as usual was received). Results revealed that the workshop condition produced larger decreases in depression over the course of the semester relative to the control condition, but only for participants endorsing higher levels of depression at baseline. Further, for participants in the workshop condition, changes in depression were negatively associated with changes in acceptance (i.e., larger increases in acceptance associated with larger decreases in depression), an association that was not statistically significant in the control group. Lastly, for participants in the workshop condition who endorsed higher levels of depression at baseline, mindfulness and values practice was associated with greater reductions in depression. Implications of these findings for future interventions are discussed.