Objective: Individuals seeking treatment for physical symptoms having unknown etiology are common in the primary healthcare setup. Factors such as biomedical, environmental, social, and psychological ones are expected to play an important role in the treatment of Medically Unexplained Physical Symptoms (MUPS). Therefore, this systematic review and meta-analysis aimed to investigate the efficacy of psychological interventions for the treatment of MUPS. Method: Studies were selected using different electronic databases (PubMed, Wiley, Cochrane), to identify RCTs published in the last 11 years on psychological interventions to treat MUPS. A total of 12 studies were finalized for systematic review and 7 for meta-analysis based on the inclusion criteria. The risk of bias was assessed by the two reviewers independently using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. OpenMeta[Analyst] was used to perform meta-analysis. Results: The findings revealed that psychological interventions can possibly be effective in treating patients with MUPS. Somatic symptom severity and depression improved in the intervention groups as compared to controls, while anxiety, and physical and mental component summary of Short-Form General Health Survey 36 did not significantly improve in the intervention group. Conclusion: A tailored module including psychological interventions to deal with these patients in primary care may be useful in improving the overall functioning of the individuals.