In this study, the formation of β-cyclodextrin derivatives (β-Cyclodextrin; β-CD, Hydroxypropyl-β-Cyclodextrin; Hβ-CD, and Sulfobutylether-β-Cyclodextrin; Sβ-CD) inclusion complexes with favipiravir (FPR) was confirmed using various spectroscopic and analytical techniques. These complexes were shown to enhance FPR solubility and antiviral activity against herpes simplex virus type 1 (HSV-1). UV–visible and fluorescence spectroscopy revealed a continuous increase in FPR absorbance and fluorescence intensity with increasing β-CD concentrations, indicating the successful formation of 1:1 inclusion complexes. The prepared β-CD solid complexes were characterized using FTIR, XRD, FESEM, and TGA-DSC, which highlighted significant surface properties, morphological changes, and improved thermal stability. Phase solubility studies demonstrated enhanced FPR solubility in the presence of the β-CDs, with stability constants (Ks) following the order: Hβ-CD (694.8 M−1) > Sβ-CD (418.4 M−1) > β-CD (364.3 M−1). In-vitro release studies showed that the Hβ-CD complex achieved a higher cumulative release of 90.16 ± 1.94 % over 90 min compared to free FPR (25.32 ± 0.29 %), attributed to its greater solubility. Molecular docking provided insights into the interaction mechanisms, revealing higher binding affinities and stability for FPR with β-CD. In-vitro antiviral assays against HSV-1 demonstrated significant viral titer reductions for free FPR with β-CDs, with Hβ-CD outperforming others due to its rapid release profile after 96 h of incubation, confirming its potential for improved antiviral formulations. The cytotoxic effects of FPR and its β-CDs inclusion complexes were evaluated on Vero cells using an MTT assay over 96 h, showing reduced cytotoxicity for the inclusion complexes compared to free FPR. Additionally, cellular uptake studies revealed that β-CDs inclusion complexes conjugated with DAPI and FITC exhibited greater intensity within Vero cells compared to free FPR.