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This paper depicts Box-Behnken design (BBD) approach to optimize the performance and emission characteristics of adjustable compression ratio, single- cylinder diesel engine with nanoparticle-blended biofuel. Cerium oxide (CeO2) nanoparticles and diethyl ether (DEE) are mixed with neem methyl ester (NME) in corresponding ratios as per BBD experimental plan. Engine performance characteristics brake thermal efficiency (BTE), brake-specific fuel consumption (BSFC), and NOx, CO, HC, and CO2 emissions have been analyzed. To study the influence of input parameters, quadratic models are developed on each output response using analysis of variance (ANOVA). Desirability function approach has been used to optimize the performance of multi-response parameters. The results revealed that nanoparticles mixed blends of NME and DEE enhances the performance characteristics and reduce the harmful emissions.