Rapid industrialization and population expansion increased the demand for petroleum-based fuels, resulting in price hike and creates serious environmental issues. Biodiesel, a clean, renewable and long-lasting alternative and for large scale production needs readily available and sustainable feedstocks. Edible and non-edible plants are abundant in Southern India, particularly Ceiba penandra (CP), Mahua longifolia (ML), and Azadirachta indica (AI), which were employed in this study in combination. An efficient heterogeneous nano-catalyst CaO-TiO2 was synthesized and employed in the transesterification process due to its recoverability and insensitivity to FFA. The catalyst was subjected to characterize by FTIR, XRD and SEM with EDX mapping. Response surface approach is engaged in this study for cost-effective production. More than 95% biodiesel yield was achieved for Ceiba penandra oil (CPO), Mahua longifolia oil (MLO), Azadirachta indica oil (AIO) and their mixture (MIO) by optimization of significant reaction parameters and the best combination was obtained as methanol oil ratio (0.32, 0.46, 0.34 and 0.42 v/v), catalyst usage (5, 6.5, 6 and 4 wt.%), mixing intensity (750, 840, 700 and 540 rpm) and duration (80, 105, 85 and 85 min) respectively with constant temperature of 70°C. Fatty acid profile was characterized by chromatograph also established the properties by ASTM and EN guidelines to confirm its compatibility in the IC engine.