Introduction: Fat-free mass (FFM) is a critical component of the human body, with implications for various diseases. Methods: We conducted a comprehensive analysis integrating a phenome-wide association study (PheWAS), a two-sample Mendelian randomization (MR) analysis, and a systematic review to investigate the associations between FFM and health outcomes. Results: PheWAS identified 183 phenotypes enriched for FFM associations, including diseases, body composition, and lifestyle factors. A two-sample MR analysis using the FinnGen and UK Biobank dataset revealed significant associations between genetically determined FFM and 36 disease outcomes, including cardiovascular diseases, metabolic disorders, and musculoskeletal conditions. The mediation MR analysis indicates that FFM indirectly influences the levels of five biomarkers in visceral adipose tissue. A systematic review identified consistent associations between FFM and several diseases, including type 2 diabetes and cervical disc disorders. Moreover, new associations such as low back pain and ovarian cancer were discovered. Conclusion: These findings challenge the conventional notion of FFM as a protective factor in health, suggesting that higher FFM levels may be linked to an increased risk of various diseases. Further clinical studies are warranted to validate these findings and elucidate the underlying mechanisms.