The potential benefit of cylinder deactivation (CDA) on power and emission performances has been numerically investigated on a locomotive 16-cylinder diesel engine. A 1D model combined with a predictive friction model and a 3D combustion model based and validated on experimental data have been developed to simulate engine working processes by deactivating half of the cylinders by cutting off the fuel supply and maintaining/cutting off valve motions. The results demonstrate that CDA with the valves closed decreases the BSFC by 11% at 450 rpm and by 14% at 556 rpm with a load of 1000 N∙m, due to increased indicated efficiency and reduced mechanical losses. After deactivating cylinders, frictional losses of piston rings increase in the active cylinders because of the raised gas pressure and the lubricating oil temperature decrease. Friction losses of the main bearings and big-end connecting rod bearings decrease due to the overall load drop. In comparison with the normal operation, CDA with the valves closed decreases the BSCO emission by 75.26% and the BSsoot emission by 62.9%. As the EGR rate is 30%, CDA with the valves closed effectively reduces the BSNOx emission to 4.2 g/(kW·h) at the cost of a 0.8% increase in the BSFC and without the rise in the BSCO emission.