Plastic waste is ubiquitously present across the world, and its nano/sub‐micron analogues (plastic nanoparticles, PNPs), raise severe environmental concerns affecting organisms’ health. Considering the direct and indirect toxic implications of PNPs, their biological impacts are actively being studied; lately, with special emphasis on cellular and molecular mechanistic intricacies. Combinatorial OMICS studies identified proteins as major regulators of PNP mediated cellular toxicity via activation of oxidative enzymes and generation of ROS. Alteration of protein function by PNPs results in DNA damage, organellar dysfunction, and autophagy, thus resulting in inflammation/cell death. The molecular mechanistic basis of these cellular toxic endeavors is fine‐tuned at the level of structural alterations in proteins of physiological relevance. Detailed biophysical studies on such protein‐PNP interactions evidenced prominent modifications in their structural architecture and conformational energy landscape. Another essential aspect of the protein‐PNP interactions includes bioenzymatic plastic degradation perspective, as the interactive units of plastics are essentially nano‐sized. Combining all these attributes of protein‐PNP interactions, the current review comprehensively documented the contemporary understanding of the concerned interactions in the light of cellular, molecular, kinetic/thermodynamic details. Additionally, the applicatory, economical facet of these interactions, PNP biogeochemical cycle and enzymatic advances pertaining to plastic degradation has also been discussed.