Antispastic medication is often used in the clinic together with physiotherapy. However, some of the antispastic drugs, e.g., baclofen and diazepam, may influence the plastic mechanisms that are necessary for motor learning and hence efficient physiotherapy. In the present study, we consequently investigated the influence of baclofen and diazepam on acquisition of a visuomotor skill. The study was designed as a semi-randomized, double-blinded, placebo-controlled, crossover study in 16 healthy human subjects. The motor skill task required the subjects to match a given force trajectory by increasing or decreasing ankle dorsiflexor torque. Subjects trained for a total of 30 min. Transcranial magnetic stimulation of the primary motor cortex leg area was applied to elicit motor evoked potentials in the anterior tibial muscle (TA). Coupling between populations of TA motor units was calculated in the frequency (coherence) domain during isometric dorsiflexion. Subjects receiving placebo showed statistically significant improvement in motor performance (q = 34.1, P = 0.014) accompanied by a statistically significant reduction in intramuscular coherence. Subjects receiving baclofen and diazepam conversely showed no progression in motor performance (P > 0.05), and the training was not accompanied by a decrease in intramuscular coherence. TA motor evoked potentials had significantly lower threshold following the training in the placebo group, whereas this was not the case in the treatment groups. These data indicate that diazepam and baclofen interfere with the acquisition of a motor skill by disrupting some of the neuroplastic changes that are involved in improved motor performance. This suggests that antispastic treatment should be used with caution in subjects receiving concomitant physiotherapy.