This study investigates the effects of neat n-butanol replacing conventional diesel fuels to enable clean combustion on a modern common-rail diesel engine. Systematic engine experiments are conducted to examine the combustion characteristics and exhaust emissions in correlation to n-butanol’s relatively high oxygen content and high volatility but low ignitability, and control strategies are thereafter developed for enabling clean and efficient combustion of neat n-butanol. Compared to its diesel counterpart, the single-shot injection of neat n-butanol offers substantially reduced NOx emissions without the use of EGR and near-zero soot emissions, but the applicable injection timing window is narrower for n-butanol limited by high maximum rates of pressure rise and/or unstable combustion. EGR is effective to reduce the combustion roughness, but it further narrows the applicable injection timing window and deteriorates the HC and CO emissions. A control strategy that deploys multi-shot injections combined with moderate use of EGR is developed and applied to improve the combustion controllability and exhaust emissions while minimizing the penalties in the engine efficiency.