Although botulinum toxin (BoNT) has been suggested as a treatment to counter neuropathic pain, no previous systematic reviews investigated the multidimensional effects of BoNT on pain relief and Health-Related Quality of Life (HR-QoL). The aim of this systematic review is to summarize the current evidence on the effectiveness of BoNT treatment for neuropathic pain, and to characterize its multidimensional effectiveness in order to guide physicians in clinical practice. Five databases were systematically searched up to 4 April 2022, to identify randomized controlled trials satisfying the following criteria: adults suffering from neuropathic pain, BoNT administration, any comparator, multidimensional assessment of pain as primary outcome, HR-QoL, physical function, anxiety and depression, and sleep quality as secondary outcomes. Twelve studies were included. The multidimensional pain scales used were short-form McGill Pain Questionnaire, Neuropathic pain scale, Neuropathic Pain Symptom Inventory, International SCI Pain Basic Data Set, West Haven-Yale Multidimensional Pain Inventory, Brief Pain Inventory, and Douleur Neuropathique 4. These scales highlighted the positive effects of BoNT administration. According to the Jadad scale, all the RCTs included were high-quality studies. BoNT administration might be effectively introduced in the comprehensive management of neuropathic pain. Further research should focus on optimal and cost-effective therapeutic protocols.