Non-nucleoside reverse transcriptase inhibitors (NNRTI) have emerged as gold standards in current anti-AIDS drug discovery and development by allosterically inhibiting HIV reverse transcriptase (HIV-RT). Connection sub-domain mutation, N348I and the M184V active site mutation decreases HIV-1 RT susceptibility to NNRTI, nevirapine (NVP), whereas concurrence of both mutations improves enzyme susceptibility to NVP. Molecular dynamics simulation and enhanced post-dynamics analyses were applied to gain molecular insight into occurrence of N348I, M184V and N348I/M184V double mutations and their effect on NVP binding landscape. Results showed that the presence of the double mutation (N348I/M184V) ameliorates the drastic effects of connection sub-domain mutation, N348I alone on NVP binding, which correlates with experimental findings. We showed that the binding of NVP to the NNRTI binding pocket (NNIBP) is drastically distorted in the presence of connection sub-domain mutation, N348I and may further explain the impaired motions of mutant RTs compared to the wild type. The residue based fluctuation further suggested that the occurrence of N348I decreased the overall flexibility of NVP-HIV-RT complex whereas concurrence of N348I/M184V double mutation restored the conformational flexibility as compared to single mutant. This phenomenon was further validated by the trends of binding free energy as well as the per-residue footprints which showed an increased ∆Gbind in case of N348I/M184V double mutant as compared to N348I variant. Further, for the first time residue interaction network highlighted the structural changes due to occurrence of M184V and N348I mutations which gives a conclusive evidence of these mutations. This work provides the most comprehensive analysis of NVP resistance and the impact of double (N348I/M184V) mutation to date from a dynamics perspective and provides information that should prove useful for understanding the drug resistance mechanism against NVP. The results also provide preliminary data which might prove useful for the design of novel inhibitors that are less susceptible to drug resistance.