Advancements in the clinical applications of small interfering RNA (siRNA) in cancer therapy have opened up new possibilities for precision medicine. siRNAs, as powerful genetic tools, have shown potential in targeting and suppressing the expression of specific genes associated with cancer progression. Their effectiveness has been further enhanced by incorporating them into nanoparticles, which protect siRNAs from degradation and enable targeted delivery. However, despite these promising developments, several challenges persist in the clinical translation of siRNA-based cancer therapy. This comprehensive review explores the progress and challenges associated with the clinical applications of siRNA in cancer therapy. This review highlights the use of siRNA-loaded nanoparticles as an effective delivery system for optimizing siRNA efficacy in various types of carcinomas and the potential of siRNA-based therapy as a genetic approach to overcome limitations associated with conventional chemotherapeutic agents, including severe drug toxicities and organ damage. Moreover, it emphasizes on the key challenges, including off-target effects, enzymatic degradation of siRNAs in serum, low tumor localization, stability issues, and rapid clearance from circulation that need to be addressed for successful clinical development of siRNA-based cancer therapy. Despite these challenges, the review identifies significant avenues for advancing siRNA technology from the laboratory to clinical settings. The ongoing progress in siRNA-loaded nanoparticles for cancer treatment demonstrates potential antitumor activities and safety profiles. By understanding the current state of siRNA-based therapy and addressing the existing challenges, we aim to pave the way for translating siRNA technology into effective oncologic clinics as an improved treatment options for cancer patients.