ABSTRACT: The objective of present research work is design and in-vivo evaluation of Erlotinib self-nanoemulsifying drug delivery system (SNEDDS) for the enhancement of oral bioavailability. Box-Behnken design was used for the study and the results analyzed using response surface methodology. Erlotinib SNEDDS were prepared with various oils, surfactants and co-surfactants and tested particle size, PDI, zeta potential, refractive index, drug release and TEM studies. The optimized Erlotinib SNEDDS has the composition of capryol 90, cremophore EL and transcutol HP. Based on the particle size and entrapment efficiency and in-vitro dissolution studies; F2 is identified as optimized formulation with 85% drug released, whereas less than 1% was released from pure drug at end time of 30 min. In-vivo bioavailability data reported in male wistar rats indicate higher concentration of drug in plasma implying enhanced systemic absorption of Erlotinib from SNEDDS formulation. The Cmax and AUC0-inf values of optimized SNEDDS was considerably higher (p<0.05) than pure drug formulation. The oral bioavailability of optimized SNEDDS increased around 12 folds when compared with pure drug. Erlotinib SNEDDS was successfully prepared, and results indicate that oral bioavailability of Erlotinib optimized SNEDDS was significantly improved when compared with pure drug. Therefore, the results suggest that the optimized formulation has a great potential for clinical application in the effective management of lymphocytic leukaemia.