Patients with multiple sclerosis (MS) often suffer from psychological distress and cognitive dysfunctioning. These factors negatively impact the health-related quality of life. Only recently behavioral therapeutic approaches are being used to treat psychological distress in MS. The aim of the present pilot study was not only to investigate the effectiveness of mindfulness-based stress reduction (MBSR) on psychological distress but also to explore whether it can improve cognitive functioning among patients with MS. Outpatients of the MS Center of the Radboud University Medical Center (Radboudumc) were invited to participate in an MBSR training. Psychological and cognitive measures were administered pre- and post-intervention. Twenty-five MS patients completed the MBSR training and psychological measures, of which 16 patients completed the cognitive tests. Significant improvements were found in depressive symptoms, quality of life, fatigue, mindfulness skills, and self-compassion. Of the cognitive tests, performance on a visual spatial processing test significantly improved after the intervention. Overall, this pilot study showed promising results of the effects of MBSR on reducing psychological distress, and it suggests MBSR might improve cognitive functioning in MS patients. Future randomized controlled trials should be conducted to confirm the possible effectiveness of MBSR—and its long-term effects—on psychological and cognitive functioning in MS patients.