A coach-guided Acceptance and Commitment Therapy (ACT) intervention that uses a blended approach of two face-to-face and five online sessions (iACT; N = 33) has been found to be more effective than a waiting-list control condition (WLC; N = 35) at enhancing the wellbeing of university students while also reducing stress and depression. The present study explored possible mediators of change that may account for the outcomes of the study. Mediation analyses revealed that changes in the non-reactivity subscale of mindfulness mediated changes in wellbeing, depression, and stress in the iACT group. In addition, changes in the sense of coherence subscale of meaningfulness mediated changes in all outcomes. Psychological flexibility and cognitive defusion did not mediate changes in outcomes. The results suggest that the use of practices focusing on non-reactivity, meaning the ability to allow thoughts and feelings to come and go without getting carried away by them, is especially important for enhancing the wellbeing of university students. A focus on enhancing meaningfulness also plays a significant role in reducing psychological distress. These findings provide a first step toward understanding the potential mechanisms of change taking place in brief, Internet-supported, blended ACT programs.