The twin crises in depletion of fossil fuels and environmental degradation have motivated researches to consolidate the use of biofuels for internal combustion engine applications. In the present study, the performance and emission characteristic of Calophyllum inophyllum oil-based methyl ester and its diesel blends are analyzed at various compression ratios. Comprehensive optimization by considering the performance parameter along with emission characteristic is rather involved and is done carefully with designed set of experiments and analyzed statistically using design expert software. Higher compression ratio (CR) induces high cylinder temperature which enhances vaporization and thereby better performance only to a certain extent, that is, up to a CR of 19. However, due to high operating temperature, the oxides of nitrogen emission increase with CR and also for high biofuel blends, but better combustion phenomenon at these conditions reduces the emissions of carbon monoxide and unburned hydrocarbon. The designed empirical statistical model for optimum performance with lower emission is found to be B30 (30% biofuel) at a CR of 19, which is then tested and validated.