Background: Adolescents' psychological stress has become an important problem. Mindfulness-based interventions (MBIs) are proven to be effective in school settings in the Western world, and so expanding MBIs further is a particularly important consideration. Objective: This study addresses the effectiveness of MBI in reducing psychological stress in Chinese school settings and the mediating role of resilience between trait mindfulness and psychological stress. Methods: This study conducts a cluster randomized controlled trial. Ninety-two middle school students in the experimental group received 10 weeks of MBI, with 10 sessions of a mindfulness course, while 97 students in the control group followed their regular school program without intervention. Results: Psychological stress, trait mindfulness, and psychological resilience were measured by the Psycho-Somatic-Tension-Relaxation Inventory (PSTRI), Five Facet Mindfulness Questionnaire (FFMQ), and Resilience Scale for Chinese Adolescents (RSCA). The results showed that (1) compared with the pretest scores of the experimental group, and the pre- and post-test scores of the control group, the post-test scores of trait mindfulness and psychological resilience in the experimental group were significantly increased, while psychological stress was significantly decreased. (2) Trait mindfulness was positively associated with psychological resilience. Trait mindfulness and psychological resilience were negatively associated with psychological stress. (3) The mediating effect of psychological resilience accounted for 43.58% of the overall effect of trait mindfulness on psychological stress. Conclusions: These findings provide encouraging evidence for MBI's effectiveness in reducing adolescents' psychological stress and the possible mediating role of psychological resilience; thus, MBI is worthy of expanding to Chinese school settings.