Despite significant advancements in therapeutic approaches, drug resistance presents a formidable challenge in the successful treatment of cancer, substantially impacting patient outcomes. Drug resistance, wherein cancer cells adapt to withstand the effects of chemotherapy is a complex mechanism influenced by several factors including drug inactivation, alteration of drug targets, drug efflux, inhibition of cell death, DNA damage repair, epithelial-mesenchymal-transition (EMT), cancer cell heterogeneity, genetic mutations, epigenetic factors, etc. Multidrug resistance (MDR) occurs when cancer cells become immune to a variety of drug types. In addition, overexpressed ATP-binding cassette (ABC) transporters which utilize energy derived from ATP hydrolysis to actively expel chemotherapy drugs from the cell, serve as a primary cause of chemotherapy-induced MDR. Furthermore, the dysregulation or abnormal activation of cellular signaling pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) PI3K/Akt/mTOR, Wnt/β-catenin, and mitogen-activated protein kinase (MAPK), significantly contributes to drug resistance by promoting survival, proliferation, and evasion of apoptosis. Therefore, targeting these pathways and processes offers a more effective therapeutic approach for cancer management.