The current investigation entails systematic development of EFV (Efavirenz) loaded isotropic mixture prepared with long chain triglycerides for obliterating food associated variability and minimizing the erratic absorption behavior. For this purpose, the optimized isotropic mixture (EF1) consists of Maisine 35-1 (20%), Transcutol HP (17.7% w/w) and Cremophor RH 40:Labrasol (1:1) (62.3% w/w) was formulated by employing D-optimal mixture design that after numerical optimization showed highest desirability of 0.995. Further, the dissolution behavior of EFV suspension in biorelevant dissolution media's simulate the fed and fasted small intestine conditions, clearly anticipated that there is an influence of food effect for EFV. However, when EFV loaded into isotropic mixture, the food effect was abolished and no significant difference was seen in biorelevant dissolution media's. The tissue distribution of EFV from EF1 follows order: blood plasma > heart > brain > lymph nodes > liver. Interestingly, the in-vivo animal pharmacokinetic performance showed positive food effect after administration of EFV suspension and marketed formulation. However, the developed formulation (EF1) nullifies this food effect. In nutshell, these studies suggested significant enhancement in the biopharmaceutical attributes of a stable and robust EFV loaded isotropic mixture.