Chemoresistance, a significant challenge in effective cancer treatment needs clear elucidation of the underlying molecular mechanism for the development of novel therapeutic strategies. Alterations in transporter pumps, oncogenes, tumour suppressor genes, mitochondrial function, DNA repair processes, autophagy, epithelial-mesenchymal transition (EMT), cancer stemness, epigenetic modifications, and exosome secretion lead to chemoresistance. Despite notable advancements in targeted cancer therapies employing both small molecules and macromolecules success rates remain suboptimal due to adverse effects like drug efflux, target mutation, increased mortality of normal cells, defective apoptosis, etc. This review proposes an advanced nanotechnological technique precisely targeting molecular determinants of chemoresistance which holds promise for enhancing cancer treatment efficacy. Further, the review explores various cancer hallmarks and pathways implicated in chemoresistance, current therapeutic modalities, and their limitations. It advocates the combination of nanoparticle-conjugated conventional drugs and natural compounds to specifically target molecular pathways that can potentially reverse or minimize chemoresistance incidences in cancer patients.