Metabolic dysfunction-associated steatotic liver disease [MASLD] is a pervasive multifactorial health burden. Post-translational modifications [PTMs] of amino acid residues in protein domains demonstrate pivotal roles for imparting dynamic alterations in the cellular micro milieu. The crux of identifying novel druggable targets relies on comprehensively studying the etiology of metabolic disorders. This review article presents how different chemical moieties of various PTMs like phosphorylation, methylation, ubiquitination, glutathionylation, neddylation, acetylation, SUMOylation, lactylation, crotonylation, hydroxylation, glycosylation, citrullination, S-sulfhydration and succinylation presents the cause-effect contribution towards the MASLD spectra. Additionally, the therapeutic prospects in the management of liver steatosis and hepatic fibrosis via targeting PTMs and regulatory enzymes are also encapsulated. This review seeks to understand the function of protein modifications in progression and promote the markers discovery of diagnostic, prognostic and drug targets towards MASLD management which could also halt the progression of a catalogue of related diseases.