The healthy heart relies on mitochondrial fatty acid β-oxidation (FAO) for ATP production but can exhibit marked metabolic flexibility in response to diverse physiological and pathological circumstances 1-4. Mutations or deficiencies in FAO enzymes can lead to a spectrum of symptoms, ranging from muscle weakness to severe cardiomyopathy, and, in some instances, culminate in neonatal/infantile mortality 5. It is generally believed that with a FAO deficit, mitochondria encounter stress, triggering the initiation of mitophagy, a process crucial for maintaining mitochondrial quality. We explored the link between FAO deficiency and mitophagy utilizing FAO-deficient mice generated through cardiomyocyte-specific deletion of carnitine palmitoyltransferase 2 (CPT2). Intriguingly, our findings revealed an unexpected decline in mitophagy in FAO-deficient hearts. Employing an integrated approach involving quantitative proteomics, metabolomics, and transcriptomics assays, we identified a suppressed PINK1/Parkin signaling pathway in CPT2-deficient heart tissues. We demonstrate that the loss of cardiac FAO impairs the PINK1 pathway by modulating the mitochondrial rhomboid protease PARL (presenilin-associated rhomboid-like protein). Furthermore, we show that inhibiting USP30, a mitochondrial deubiquitinating enzyme antagonizing PINK1/Parkin function, restores cardiac mitophagy, thereby alleviating FAO deficiency-associated cardiac dysfunction. Notably, the deletion of USP30 confers a significant survival advantage to FAO-deficient animals, doubling the median survival and substantially improving the maximum survival rate. This study therefore unveils a novel connection between FAO and PINK1-dependent mitophagy. These findings also delineate a potential therapeutic avenue for addressing rare FAO-deficient cardiomyopathies, as well as a potential strategy for more routine heart failure, a condition often characterized by impaired fatty acid metabolism.