Cancer cells often evade cell death pathways involved in the maintenance of tissue homeostasis, rendering them an advanced and aggressive form along with resistance to therapeutic modalities. Dysregulation in the pathways has been established as the main contributor to these escaping behaviors. Hence, targeting them with active molecules has gained impetus in the last few decades, and to date, numerous research studies have shown the promising efficacy of several small molecules. This review emphasizes the important cell-death mechanisms such as apoptosis, mitochondrial-driven death, parthanatos, and ferroptosis and how they can be targeted for cancer therapy. It highlights FDA-approved drugs, including olaparib and arsenic trioxide, as well as investigational compounds such as lupeol and berberine and compounds in clinical trials like SLAMF7 and chloroquine. Although these strategies exhibit significant potential, the sustained therapeutic efficacy is limited by the resistance mechanisms, like the upregulation of anti-apoptotic proteins and activation of adaptive survival pathways. This review also highlights the need to exploit multi-targeted approaches like combinatorial therapies along with the integration of multi-omics and AI-driven strategies in order to better understand the mechanisms involved in cell death and to develop therapeutic protocols, prognosis biomarkers, and drug delivery systems for enhancing therapeutic outputs.