Background and Purpose Botulinum Neurotoxin type A1 (BoNT/A) is one of the most potent neurotoxins known. At the same time, it is also one of the safest therapeutic agents used for the treatment of several human disorders and in aesthetic medicine. Notwithstanding great effectiveness, strategies to accelerate the onset and prolong BoNT/A action would significantly ameliorate its pharmacological effects with beneficial repercussions on clinical use. Experimental Approach Here, we combined BoNT/A with two fast-acting inhibitors of excitation-contraction coupling (ECCI), either the µ-conotoxin CnIIIC or dantrolene, and tested the effect of their co-injection on a model of hind-limb paralysis in rodents using behavioral, biochemical, imaging and electrophysiology assays. Key Results We report that the BoNT/A-ECCI combination accelerated the onset of muscle relaxation. Surprisingly, it also potentiated the peak effect and extended the duration of the three BoNT/A commercial preparations onabotulinumtoxinA, abobotulinumtoxinA and incobotulinumtoxinA. We found that ECCI co-injection increased the number of BoNT/A molecules entering motoneuron terminals, which induced a faster and larger cleavage of SNAP-25 during the onset and peak phases, and prolonged the attenuation of nerve-muscle neurotransmission during the recovery phase. We estimate that ECCI co-injection yields a three-fold potentiation in BoNT/A pharmacological activity. Conclusions and Implications Overall, our results show that the pharmacological activity of BoNT/A can be combined and synergized with other bioactive molecules and uncover a novel strategy to enhance BoNT/A neuromuscular effects without altering the neurotoxin moiety or intrinsic activity, thus maintaining its exceptional safety profile.