The ubiquitin-proteasome system (UPS) and mitochondria play a vital role in maintaining cellular homeostasis. Mitochondria, as the primary energy source in eukaryotic cells, generate adenosine 5′-triphosphate (ATP) through oxidative phosphorylation. This energy is essential for various cellular processes, including protein quality control mechanisms like the UPS. The UPS, responsible for targeted protein degradation, requires ATP for ubiquitin activation, conjugation, and proteasomal degradation. Mitochondrial dysfunction can lead to decreased ATP production, impairing UPS efficacy and potentially causing the accumulation of misfolded proteins. Additionally, UPS impairment can affect mitochondrial dynamics, morphology, and function by disrupting the turnover of mitochondrial proteins. A complex relationship between mitochondrial function, UPS activity, and mitophagy dysfunction in one system affects others. Mitophagy-the selective autophagy of damaged mitochondria. UPS mediates the regulation of mitochondrial fission and fusion through the degradation of key proteins such as dynamin-related protein 1, mitofusion1, and mitofusion2, critical for maintaining mitochondrial network health and adapting to cellular demands. Mitophagy is regulated by proteins such as PINK1 and Parkin, which selectively remove damaged mitochondria, preserving mitochondrial membrane potential (∆Ψm) and cellular viability. Targeting the interplay through mitochondrial enhancers or UPS modulators presents a promising therapeutic approach in numerous diseases such as neurological disorders, cardiovascular diseases, metabolic reprogramming, and cancer.