This study examined the effects of extrusion conditions of Feed moisture (FM) (14 – 25% wb) and Screw speed (SS) (250 – 350 rpm) at constant barrel temperature of 100oC on some chemical composition and functional properties of thermo-extrudates from three sesame varieties (Bogoro, E8, and Ex-Sudan), using central composite rotatable design on water absorption (WAC) and oil absorption (OAC) capacity, bulk density (BD), solubility (SOL) and swelling capacity (SC). The protein content of thermo-extrudates significantly (p<0.05) decreased with FM and increased SS. The tannin content in the thermo-extrudates ranged from 11.0 to 14.17; 9.83 to 12.50; and 7.50 to 12.65 (mg/100 g), the phytate content ranged from 19.33 to 25.00; 17.00 to 21.50 and 16.0 to 22.83 (mg/100 g) in Bogoro, E8, and Ex-Sudan respectively. An increase in FM and SS (p<0.05) reduced tannin by 41%, 40% and 46%, and phytate by 28%, 32%, and 30% in Bogoro, E8,and Ex-Sudan. Solubility was the most predictable functional property of the thermo-extrudates, with models having coefficients of determination (R2) of 0.99, 0.82, and 0.86 for Bogoro, E8, and Ex-Sudan. The optimized processing conditions for E8 with desirability of 0.74 are FM 14% and SS 250 rpm, which resulted in optimal WAC of 168.55%; SOL 14.36%; OAC 138.27%; BD 0.67 g/cm3; SC 1.53%.