The recent interest in alternative non-fossil fuels has lead researchers to evaluate several alcohol-based formulations. However, one of the main requirements for innovative fuels it to be compatible with existing units’ hardware, so that full replacement or smart flexible-fuel strategies can be smoothly adopted. N-Butanol is considered as a promising candidate to replace commercial Gasoline, given its ease of production from bio-mass and its main physical and chemical properties similar to those of Gasoline. The compared behaviour of n-Butanol and Gasoline was analysed in an optically-accessible DISI engine in a previous paper. CFD simulations confirmed the main outcomes of the experimental campaign in terms of combustion behaviour for two operating conditions; in particular, the first-order role of the slower evaporation rate of n-Butanol compared to Gasoline was highlighted when the two fuels were operated under the same injection phasing. The poor n-Butanol/air mixture homogeneity was found to be a major limiting factor of the potential benefit from the use of n-Butanol. In this paper this aspect is deepened by numerically exploring different mixture preparation strategies for n-Butanol. This is obtained by variation of the injection phasing and profile, including the use of multiple injection strategies. An optimized fuel injection strategy is then numerically identified considering mixture homogeneity, engine torque output and tailpipe emissions. Finally, this strategy is experimentally tested to confirm CFD results and conclusions are drawn on the optimized use of n-Butanol in modern GDI units.