This study presents the first messenger RNA (mRNA) therapy for metastatic ovarian cancer and cachexia‐induced muscle wasting based on lipid nanoparticles that deliver follistatin (FST) mRNA predominantly to cancer clusters following intraperitoneal administration. The secreted FST protein, endogenously synthesized from delivered mRNA, efficiently reduces elevated activin A levels associated with aggressive ovarian cancer and associated cachexia. By altering the cancer cell phenotype, mRNA treatment prevents malignant ascites, delays cancer progression, induces the formation of solid tumors, and preserves muscle mass in cancer‐bearing mice by inhibiting negative regulators of muscle mass. Finally, mRNA therapy provides synergistic effects in combination with cisplatin, increasing the survival of mice and counteracting muscle atrophy induced by chemotherapy and cancer‐associated cachexia. The treated mice develop few nonadherent tumors that are easily resected from the peritoneum. Clinically, this nanomedicine‐based mRNA therapy can facilitate complete cytoreduction, target resistance, improve resilience during aggressive chemotherapy, and improve survival in advanced ovarian cancer. Through the suppression of negative regulators of muscle mass and modulation of ovarian cancer cluster morphology, follistatin mRNA lipid nanoparticle treatment prevents malignant ascites, enhances solid tumor form, delays cancer progression, and preserves muscle mass in cancer‐bearing mice. Follistatin mRNA treatment increases mice survival while decreasing chemotherapy‐induced muscular atrophy and cancer‐associated cachexia.