Recent advancements in the cellular and molecular understanding of cancer biology have significantly increased the probability of managing uncontrolled cancer cell proliferation. Advancements in combinational drug delivery at a minimal dose in tumor reduction are providing alternative therapeutic approaches in the clinical management of different cancer types over traditional anticancer treatment regimes. In contrast, an emerging paradigm in RNA interference (RNAi)-based therapeutics has been under study for a few decades to overcome the limitation of conventional cancer therapy by targeting cancer at its genetic and epigenetic levels. The intricate crosstalk among multifaceted signaling and effector pathways in cancer has long been recognized, and the adaptability of this network to evade single-target interventions using RNAi in cancer treatment is driving the advancement of combinational RNAi-based therapies. Therefore, researchers are exploring combinations of small interfering RNA (siRNA), microRNA (miRNA), and other small RNAs to silence multiple genes simultaneously, offering a potential solution to treat ever-evolving cancer by overcoming resistance mechanisms of cancer cells. This review endeavors to bring attention to the rationale of combinational cancer therapy using RNAi-based therapeutics for effective cancer treatment. Here, we provide a comprehensive analysis of multigene targets designed for blocking different tumor-associated cellular functions. Our systematic analysis of preclinical tumor inhibition studies shows that combinational RNAi therapy outperforms by reducing the average tumor volume to 22.85% compared to that of 54.75% when treated with single RNAi therapies. Finally, we highlight the challenges and future perspectives inherent in the formulation of combinational RNAi-based therapies. Overall, this review underscores the potential of combinational RNAi-based therapy and may serve as a reference for researchers in the selection of precise and efficient RNAi combinations, promoting ongoing advancements in cancer treatment.