Hypoxia-inducible factor-1 alpha (HIF-1α) is an important transcription factor regulating glycolysis, angiogenesis, metastasis, and erythropoiesis under hypoxic conditions in solid tumors. Small interfering RNAs (siRNAs) have emerged as a promising therapeutic approach for solid tumors by selectively silencing target genes. This study explored siRNA-mediated degradation of HIF-1α by specifically targeting HIF-1α mRNA. We retrieved the HIF-1α gene sequence from the database and used various computational tools like siDirect and OligoWalk to get potential 19-21nts long siRNAs. Furthermore, these siRNAs were screened using parameters like sequence specificity, BLASTn, secondary structure formation, GC content, binding affinity between siRNA and mRNA, and thermodynamic properties. The potential siRNAs were further evaluated through molecular docking studies for interaction with the human Argonaute-2 protein (hAgo2), followed by molecular dynamics simulation studies. Post-MD studies revealed S4 (5'UAUAUGGUGAUGAUGUGGC3') as the most potential siRNA candidate against HIF-1α, based on root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and H-bond analysis. Molecular mechanics Poisson-Boltzmann surface area (MMPBSA) analysis was also performed to further validate the selected siRNA candidates, which further affirmed S4 (5'UAUAUGGUGAUGAUGUGGC3') as a potential candidate against HIF-1α.