Herbal medicines demonstrate clinical promise for cancer treatment. Protein post translational modifications (PTMs) regulate tumorigenesis and cancer progression. While PTMs contributing to cancer are well-studied, the precise mechanisms and defined targets of herbal medicines on PTM-associated carcinogenesis remain unclear. Hence, comprehensively understanding how PTMs regulate cancer hallmarks is crucial to elucidate the pharmacological mechanisms of herbal medicines for cancer treatment. Advanced development in highly sensitive mass spectrometry (MS)-based techniques has helped utilize PTM-focused studies on cancers. Accumulating evidence has been achieved in laboratory to ascertain the biological mechanism of herbal medicines in cancer therapy. Implication of the strong association between cancer and PTM makes new perspective to comprehend the intricate dialogues between herbal medicines and cellular contexts. Complex components of herbal medicines limit the benefits of herbal-based cancer therapies. In this review, we address that PTMs add a layer of proteomic complexity to the cancer through altering the protein structure, expression, function, and localization. Elaborating PTM implicated in cell signaling, apoptosis and transcriptional regulation function, and the possible cellular signaling, have provided important information about the mechanism of many herbal therapies. Continued optimization of proteomic strategies for PTM analysis in herbal medicines are also discussed. Rigorous evaluations of herbal medicines and the chemoproteomic strategies are necessary to explore the aberrant regulation of PTM dynamics contributed to the cancer development and herbal associated pharmacological issues. These efforts will eventually help develop more herbal drugs as modern therapeutic agents.