Sphingosine kinase 1 (SphK1) is an essential enzyme in sphingolipid metabolism, catalyzing the phosphorylation of sphingosine to produce sphingosine-1-phosphate (S1P), a bioactive lipid with diverse roles in cell proliferation, survival, and migration. Dysregulation of the SphK1/S1P axis is implicated in a variety of pathological conditions, including inflammatory, metabolic, and neurodegenerative diseases. Targeting SphK1 represents a promising therapeutic strategy, particularly in oncology and inflammation-related pathologies. In this study, we investigated the potential of three natural compounds, Baicalin (BA), Naringenin (NR), and Noscapine (NS) as SphK1 inhibitors. Through combined molecular docking, molecular dynamics simulations, binding studies and enzyme inhibition assays, we identified these compounds as effective SphK1 inhibitors. BA, NR, and NS exhibited binding affinities characterized by IC50 values of 26.542, 32.157, and 28.134 μM, respectively. These molecules bind to the active site of SphK1 with favorable binding energies with strong non-covalent interactions. This study provides structural and functional insights into potential of BA, NR, and NS to target SphK1 selectively, which can function as lead compounds for developing novel anti-cancer therapy with minimal off-target effects, offering avenues for developing drugs with enhanced specificity and affinity for this enzyme.