The objective of the present study was to improve the oral bioavailability using high-density gastro-retentive pellets containing solid dispersion of acyclovir. Solid dispersion prepared with polyvinylpyrrolidone (PVP K30) and hydroxypropyl methylcellulose (HPMC) using different ratios 1:1, 1:2, 1:3, 1:4, and 1:5 by solvent evaporation method and characterized for solubility study, dissolution study, FT-IR, DSC, and XRD. High-density gastro-retentive pellets containing solid dispersion of acyclovir was prepared by extrusion/spheronization technique using solid dispersion of acyclovir with PVP K30 (1:3), Barium sulphate as high-density material, microcrystalline cellulose (MCC) as extrusion aid, ethylcellulose (EC) as release retarding polymer and HPMC as swellable gel-forming polymer. The formulation was optimized based on in-vitro release profile and characterized for pellets morphology, micro-meritics properties, FT-IR, DSC, XRD, and in-vivo study. The optimized formulation F8f showed the release for 12 h with an increase in retention at the absorption site. Release kinetic studies of optimized formulation showed that the data best fit in Higuchi's model. The in-vivo studies like pharmacokinetic parameters and X-ray transmission were investigated in Wistar rats. The pharmacokinetic study shows that the bioavailability of high-density gastroretentive pellets containing solid dispersion of acyclovir can be increased as compared to a plain drug, marketed formulation, and solid dispersion. The X-ray analysis further ensures that the optimized formulation is retained at the bottom of the stomach, which is essential to improve the absorption window of acyclovir. INTRODUCTION: Acyclovir is an antiviral drug used for the management and cure of herpesviruses [HSV-I] & [HSV-II] and varicella-zoster virus. The mechanisms of its antiviral activity include inhibition of viral DNA polymerase, DNA polymerase inhibition, adding into, and abortion of the developing viral DNA chain 1 .