Over the years, alternative and complementary medicine have garnered much attention all across the globe. To this end, phytochemicals have intriguing potential against myriads of disease conditions; nevertheless, as of yet, the molecular intricacies for their therapeutic potential is incompletely understood. It is widely acknowledged that proteomics technology has been explored as a reliable approach to understand the molecular intricacies related to phytochemi-cal-based therapeutic interventions. Reckoning with this, the present review provides an overview of the proteomics studies performed to unravel the underlying molecular intricacies of various phytochemicals such as Curcumin, Genistein, and Tanshinone IIA. Abstract: Phytochemicals possess various intriguing pharmacological properties against diverse pathological conditions. Extensive studies are ongoing to understand the structural/functional Cancers 2023, 15, 249. https://doi.org/10.3390/cancers15010249 https://www.mdpi.com/journal/cancers Cancers 2023, 15, 249 2 of 45 properties of phytochemicals as well as the molecular mechanisms of their therapeutic function against various disease conditions. Phytochemicals such as curcumin (Cur), genistein (Gen), and tanshinone-IIA (Tan IIA) have multifaceted therapeutic potentials and various efforts are in progress to understand the molecular dynamics of their function with different tools and technologies. Cur is an active lipophilic polyphenol with pleiotropic function, and it has been shown to possess various intriguing properties including antioxidant, anti-inflammatory, anti-microbial, anticancer, and anti-genotoxic properties besides others beneficial properties. Similarly, Gen (an isoflavone) exhibits a wide range of vital functions including antioxidant, anti-inflammatory, pro-apoptotic, anti-proliferative, anti-angiogenic activities etc. In addition, Tan IIA, a lipophilic compound, possesses antioxidant, anti-angiogenic, anti-inflammatory, anticancer activities, and so on. Over the last few decades, the field of proteomics has garnered great momentum mainly attributed to the recent advancement in mass spectrometry (MS) techniques. It is envisaged that the proteomics technology has considerably contributed to the biomedical research endeavors lately. Interestingly, they have also been explored as a reliable approach to understand the molecular intricacies related to phytochemical-based therapeutic interventions. The present review provides an overview of the proteomics studies performed to unravel the underlying molecular intricacies of various phytochemicals such as Cur, Gen, and Tan IIA. This in-depth study will help the researchers in better understanding of the pharmacological potential of the phytochemicals at the proteomics level. Certainly, this review will be highly instrumental in catalyzing the translational shift from phytochemical-based biomedical research to clinical practice in the near future.