Elucidation of the mechanisms that cause cardiac hypertrophy is essential for developing novel therapeutic strategies to prevent or reverse these prevalent conditions. Prdm16/Mel1 (PRDM16) belongs to the Prdm family of transcription factors involved in cell fate determination and development. PRDM16 deletion, found in humans with 1p36 deletion syndrome, has been associated with two main cardiomyopathies: left ventricle non-compaction (LVNC) and dilated cardiomyopathy. Nonetheless, its role in the heart and the underlying mechanisms by which these mutations contribute to the development of cardiomyopathy are unknown. We sought to directly assess the role of Prdm16 in the developing and adult heart by generating both a germline (cPRDM16) and a tamoxifen-inducible (ciPRDM16) cardiomyocyte-specific Prdm16 knockout mice. cPRDM16KO mice died shortly after birth, showing grossly abnormal ventricles that were reduced in size and often exhibiting a cleft at their apex, consistent with LVCN. Both heterozygous mice (cPRDM16KOhet) and ciPRDM16KO are viable and displayed markedly increased heart size, cardiomyocyte cross sectional area, collagen deposition and expression of genes involved in cardiac hypertrophy and ECM production. We observed an increased in TGF-β receptors mRNA expression as well as activation of Smad signaling in the hearts of cPRDM16KO neonates, cPRDM16 heterozygous, and ciPRDM16 KO mice. Interestingly, we observed a systematic reduction in Drp1 phosphorylation on Ser616 (activation) in the hearts of cPRDM16KO and cPRDM16het mice. The reduction in Drp1 phosphorylation was associated with more tubular mitochondria in cPRDM16KO mice. Interestingly, by 25 weeks, cPRDM16het mice accumulated more mitochondrial proteins, despite exhibiting no change in PGC1α. Together, these data reveal previously unknown roles for Prdm16 in protection against cardiac hypertrophy and fibrosis through the suppression of TGF-β/Smad signaling in the heart. They also reveal roles for PRDM16 in the modulation of mitochondrial dynamics and clearance in the heart, a process that likely involves the fission protein Drp1.