The paper presents an innovative method combining artificial neural networks (ANNs) with Fuzzy PID to demonstrate the advantages of this control approach for meeting both NOx emission requirements and NH3 slip targets. An ANN model was utilized to simulate the formation of NOx emissions under various engine operating conditions. Next, an effective closed-loop control strategy with a type of feedback known as fuzzy PID is adopted for on-line, real-time control of 32.5% aqueous urea dosing in the exhaust stream. The new strategy explores the benefits by simulation and testing in the environments of Matlab/Simulink and ESC/ETC, respectively. The notable achievement of considerable NOx reduction and an acceptably small NH3 slip is obtained based on this new, feasible and effective strategy.