Objectives: The aims of the present study were two-fold: to investigate whether, compared to an active control condition, a modified mindfulness-based stress reduction (MBSR) program could (1) reduce symptoms of stress and depression, and (2) regulate salivary cortisol and serum creatine kinase (CK) concentrations, two physiological stress markers. Methods: Thirty male wrestlers (Mage= 26.73 years) were randomly assigned either to the MBSR intervention or the active control condition. Both at the beginning and at the end of the intervention, the participants completed questionnaires on perceived stress and depression; in parallel, salivary samples were collected to measure cortisol in saliva, while blood samples were collected to assess serum CK. The study lasted for eight consecutive weeks. The intervention consisted of 16 group sessions (90 min each); the active control condition had an identical schedule, though without bona fide interventions. During the study period, the participants kept their sleeping, nutritional and exercising schedules unaltered. Results: Over time, symptoms of stress and depression decreased; the level of decrease was more prominent in the MBSR condition than the active control condition (significant p values and large effect sizes of interaction). Further, cortisol and creatine kinase concentrations also decreased more in the MBSR condition compared to the active control condition (large effect sizes of interaction). Conclusions: The present study’s findings suggest that among male wrestlers, a modified MBSR intervention have the potential to reduce both psychological (stress and depression) and physiological (cortisol and creatine kinase) indices as compared to an active control condition.