The subcutaneous administration of insulin fails to imitate the natural insulin release from the pancreas and is commonly associated with pain and chance of infection at the site of infection. The present research study aimed to formulate a PEI-surface-modified inclusion complex of human insulin with 2-hydroxypropyl-β-cyclodextrin and load it into SNEDDS to increase the oral bioavailability of insulin and enhance patient compliance. The inclusion complex was prepared based on the principle of Schiff-base reaction using co-precipitation method. The optimized formulation of SNEDDS (SP1) consisted of oleic acid, propylene glycol, and Tween 20. The complex-loaded SNEDDS (SPC7-SP1) exhibited particle size of 304.33 ± 2.27 nm and zeta potential of -22.60 ± 5.09 mV. The in-vivo bioactivity and bioavailability studies in Sprague-Dawley rats showed a maximum blood glucose reduction up to 63% of the initial glucose levels at 6 h after oral administration of SPC7-SP1 as compared to the s.c. administration of which humulin R showed blood glucose reduction up to 53 % of the initial levels at 2 h. The pharmacokinetic parameters observed for SPC7-SP1 were t_1/2=38.32 h, t_max=4 h, C_max=7.94 mU/mL, and AUC_0-24=104.54 mU/mL*h. The results demonstrated that a combination of inclusion complex and SNEDDS possesses the potential to serve for oral administration of insulin.