Cancer is a therapeutically challenging and genomically complicated disease. Pioneering studies have uncovered multifaceted aspects of cancer, ranging from intra- and inter-tumor heterogeneity, drug resistance, and genetic/epigenetic mutations. Loss of apoptosis is another critical aspect that makes cancer cells resistant to death. A substantial fraction of mechanistic information gleaned from cutting-edge studies has enabled researchers to develop near-to-complete resolution of the apoptotic pathway. Within the exciting frontiers of apoptosis, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) has garnered phenomenal appreciation by interdisciplinary researchers principally because of its unique capability to target cancer cells. TRAIL-based monotherapies and combinatorial therapies have reached phase II and phase III clinical trials. Rapidly upgrading the list of clinical trials substantiates the clinically valuable role of TRAIL-based therapeutics in cancer therapy. However, there is a growing concern about the poor bioavailability and rapid clearance of TRAIL-based therapeutics. Excitingly, the charismatic field of nanotechnology offers solutions for different problems, and we have witnessed remarkable breakthroughs in the efficacy of TRAIL-based therapeutics using nanotechnological approaches. In this review, we have attempted to provide a summary about different nanotechnologically assisted delivery methods for TRAIL-based therapeutics in cell culture studies and animal model studies for the inhibition/prevention of cancer.