Reactive and non-reactive wettings of pure Al and Al–Ni alloy droplets on an NiAl(100) substrate were numerically investigated. The embedded atoms method potentials were applied to account for interatomic interactions for the Al–Ni systems. The results show that since the Al–Ni alloy droplets has lower equilibrium contact angle, their spreading on the substrate will be slightly faster than the pure Al droplet. However, owing to atom interdiffusion effects on the relaxed substrate, enhanced dissolution of Ni atoms from the substrate to the droplet would remarkably accelerate the spreading using rigid substrate as control. Thus, the pure Al droplet yields the fastest spreading due to its corresponding farthest-from-equilibrium concentration, which is followed by 90% Al-10% Ni droplet and 80% Al-20% Ni droplet. The enhanced spreading kinetics is attributed to the decreased bulk viscous dissipation and local dissipation in the vicinity of the contact line caused by the dissolution.