Advent of proteomic techniques has made it possible to identify a broad spectrum of proteins in living systems. Studying the impact of nanoparticle (NP)-mediated plant protein responses is an emerging field. NPs are continuously being released into the environment and directly or indirectly affect plant's biochemistry. Exposure of plants to NPs, especially crops, poses a significant risk to the food chain, leading to changes in underlying metabolic processes. Once absorbed by plants, NPs interact with cellular proteins, thereby inducing changes in plant protein patterns. Based on the reactivity, properties, and translocation of nanoparticles, NPs can interfere with proteins involved in various cellular processes in plants such as energy regulation, redox metabolism, and cytotoxicity. Such interactions of NPs at the subcellular level enhance ROS scavenging activity, especially under stress conditions. Although higher concentrations of NPs induce ROS production and hinder oxidative mechanisms under stress conditions, NPs also mediate metabolic changes from fermentation to normal cellular processes. Although there has been lots of work conducted to understand the different effects of NPs on plants, the knowledge of proteomic responses of plants toward NPs is still very limited. This review has focused on the multi-omic analysis of NP interaction mechanisms with crop plants mainly centering on the proteomic perspective in response to both stress and non-stressed conditions. Furthermore, NP-specific interaction mechanisms with the biological pathways are discussed in detail.