The effect of physical manipulation on the outcome of neurotoxin (NT) injection was studied in a rat tibialis anterior (TA) model system where dorsiflexion torque could be measured precisely. After determination of initial torque, all rats received a one-time botulinum toxin A (BTX-A) injection (dose 6.0 units/kg in a volume of 100μL) into the TA midbelly. Four experimental groups were studied: one group was subjected to BTX-A injection alone (BTX-A only, n=8), one was subjected to BTX-A injection followed immediately by 10 isometric contractions (ISO; n=9), and the third was subjected to BTX-A followed immediately by 10 muscle passive stretch/release cycles (PS; n=10). After 1 month, maximum dorsiflexion torque of the injected and contralateral legs was determined followed by quantification of TA fiber area. Post-injection torque was significantly reduced by around 80% in all NT-treated extremities 1 month after injection (p<0.05). While all NT-treated extremities demonstrated a significant torque decrease relative to their pre-injection levels, ISO and PS groups demonstrated significantly lower torques compared with the BTX-A only group which received no physical manipulation (p<0.05) indicating greater efficacy. Perhaps even more surprising was that the ISO and PS groups both demonstrated a significantly smaller contralateral effect compared with the BTX-A only group that received no manipulation (p<0.05) indicating a decreased systemic-effect. Muscle fiber size generally correlated with dorsiflexion torque. These data demonstrate that both neuromuscular activity (seen in the ISO group) and muscle movement (seen in the PS group) increased the efficacy of BTX-A and decreased the systemic side effects.