Protein post-translational modifications (PTMs), serving as crucial molecular switches regulating protein function and signaling pathways, have emerged as a research hotspot for elucidating the pathogenesis of Ischemic heart disease (IHD) and devising targeted therapeutic approaches. This review provides a comprehensive overview of the principal PTM types associated with IHD, encompassing phosphorylation, acetylation, ubiquitination, SUMOylation, glycosylation, lactylation and succinylation. It also delves into the molecular mechanisms and key targets of PTMs in IHD pathology, primarily involving myocardial energy metabolism, calcium homeostasis, inflammatory responses, cell death, and myocardial fibrosis. Additionally, this paper evaluates the prospective applications of specific kinase modulators, PTM-targeting modifiers, and gene editing technologies in the treatment of IHD, and proposes a “modificatomics”-oriented precision intervention strategy, which offers a novel perspective for the management of IHD.