HIV drug resistant mutations that render the current Highly Active Anti-Retroviral Therapy (HAART) cocktail drugs ineffective are increasingly reported. To study the mechanisms of these mutations in conferring drug resistance, we computationally analyzed 14 reverse transcriptase (RT) structures of HIV-1 on the following parameters: drug-binding pocket volume, allosteric effects caused by the mutations, and structural thermal stability. We constructed structural correlation-based networks of the mutant RT–drug complexes and the analyses support the use of efavirenz (EFZ) as the first-line drug, given that cross-resistance is least likely to develop from EFZ-resistant mutations. On the other hand, rilpivirine (RPV)-resistant mutations showed the highest cross-resistance to the other non-nucleoside RT inhibitors. With significant drug cross-resistance associated with the known allosteric drug-binding site, there is a need to identify new allosteric druggable sites in the structure of RT. Through computational analyses, we found such a novel druggable pocket on the HIV-1 RT structure that is comparable with the original allosteric drug site, opening the possibility to the design of new inhibitors.