Nanoparticles (NPs) have emerged as promising tools in modern agriculture, offering potential solutions to enhance plant growth, nutrient uptake, pest control, and stress tolerance. Due to their unique properties, such as large surface area and high reactivity, NPs are capable of interacting at the molecular level, providing mechanisms to mitigate abiotic stresses, including environmental contaminants, water scarcity, and natural calamities, which jeopardize global crop production. Despite their potential, the molecular mechanisms underlying NP-plant interactions, particularly under stress conditions, remain poorly understood, highlighting the need for further investigation. Proteomics, which involves the study of proteins and their functions, provides a powerful approach to investigating the molecular responses of plants to NP exposure. Advanced mass spectrometry (MS)-based techniques enable the identification and quantification of proteins, as well as the analysis of post-translational modifications (PTMs) that regulate stress-responsive pathways. Techniques such as SILAC, iTRAQ, and label-free quantification offer precise measurements of protein abundance changes in response to NP treatments. Furthermore, proteomics-based approaches, including multiple reaction monitoring (MRM), enable the validation of key proteins involved in stress adaptation. The integration of proteomics with other omics technologies offers a comprehensive understanding of NP-induced molecular changes and unveils complex regulatory networks involved in stress tolerance. Although challenges, such as the complexity of plant proteomes and low-abundance protein detection, persist, advancements in MS sensitivity and computational proteomics are addressing these obstacles. This chapter examines the combined potential of NPs and proteomics to enhance crop resilience, focusing on key proteins and signalling pathways involved in stress tolerance, with the goal of providing sustainable agricultural solutions in the face of increasing abiotic stresses.