<p>Skeletal muscle (SkM) atrophy is an associated disorder of cachexia, sarcopenia, immobilization, and denervation and is responsible for increased mortality and morbidity. SkM atrophy is often characterized by increased protein degradation and decreased protein synthesis in skeletal muscle. Increased protein catabolism is firmly associated with protein ubiquitination, an associated post-transcriptional modification of proteins that mediate diverse cellular functions like cell growth, cell death, DNA damage repair, and protein degradation. During the SkM atrophy, the extents of ubiquitination decide the degradative pathway of proteins as well as organelles. The ubiquitination process is regulated by three enzymes, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and an E3 ubiquitin ligase (E3) to mediate the transfer of ubiquitin to the Lys residue of the targeted protein. More than 600 E3 ligases (Reviewed Uniprot Database) known to date are tissue-specific, organ-specific, and ubiquitous. Hence, E3 ligases may be selective drug targets due to their involvement in the regulation of stabilities and functions of proteins. Muscle atrophy F-box protein (MAFbx)/atrogin-1, and E3 ubiquitin-protein ligase <i>TRIM63</i> (MuRF-1) are highly explored muscle-specific E3 ligases. However, the inhibition of MAFbx and MuRF-1 cannot stop the muscle atrophy completely. Hence, the involvement of other highly expressed E3 ubiquitin-protein ligases in SkM i.e., TRIM7, UBE2O, MIB2, and CHIP are also important factors in SkM atrophy. Hence, this review aimed to highlight the interplay and importance of E3 ligases in SkM atrophy.</p>