Aim of this study was to improve nevirapine solubility using solid dispersion technique and applying molecular modeling to assess drug-polymer interactions.Solid dispersions were prepared usingEudragit S100 and HPMC K4M by solvent evaporation. Schrodinger 2021-3 softwarewas used to compute solubility parameters and drug polymer interactions. Spectral and thermal studies were used to evaluate interaction of nevirapine with polymers. Saturation solubility and dissolution studies were performed. FTIR and PXRD investigations revealed amorphization of NVP in solid dispersions. DSC thermograms further confirmed this. NVP-HPMC K4M solid dispersion displayed significantly higher solubility than with Eudragit S100 (ES100). Hansen and Hildebrand solubility parameters revealed greater affinity of NVP with HPMC K4M than with ES100. Interaction studies revealedgreater number of hydrogen bonds between NVP and HPMC K4M than with ES 100. In vitro and molecular modeling studies thus revealed that NVP showed higher solubility with HPMC K4M than with ES100.