Botulinum toxin type A (BoNT-A) is considered the gold standard for the treatment of focal post-stroke spasticity (PSS). However, a recently published study estimated that a significant percentage of patients affected by PSS could benefit from higher doses of BoNT-A than those permitted by current directives in the countries studied. Several studies have reported the use of high doses of BoNT-A in the management of patients affected by severe PSS; however, the most important adverse effect of this drug might be systemic diffusion of the toxin, which could potentially be related to its dose. Even if systemic toxicity is a rare event, fear of systemic toxicity is still the most relevant concern regarding use of high doses. The aim of our narrative review was to show the state of the art on the use of high doses of BoNT-A in patients affected by PSS in order to define the safety profile, focusing on both clinical and instrumental assessment of systemic effects. Current evidence from the literature suggests that higher doses of BoNT-A are effective in reducing spasticity of upper and lower limbs after stroke, with rare occurrence of mild adverse effects. The use of high doses seems to be an effective and safe therapeutic option to reduce multifocal or generalized PSS in selected patients. In particular, the potential role of higher doses in order to improve the functional outcome of these patients should be noted.