Background: Botulinum neurotoxins (BoNTs) have transitioned from being one of nature’s deadliest poisons to one of medicine’s most versatile therapeutic agents. Since their first medical application, neuromodulators have demonstrated remarkable efficacy and safety across therapeutic and aesthetic indications. However, systemic, or iatrogenic botulism, though rare, underscores the need for effective reversal strategies. Objective: This chapter aims to examine current and emerging pharmacologic interventions for reversing or lessening the effects of botulinum neurotoxin in a clinical setting. Methods: A narrative review of the literature was undertaken, reviewing animal and human studies, focusing on the evaluation of pharmacologic and biologic agents investigated for BoNT reversal, antitoxins, monoclonal antibodies, cholinesterase inhibitors, and experimental receptor antagonists. Results: The only FDA-approved systemic antitoxin remains the equine-derived heptavalent Botulism Antitoxin (BAT), which neutralises circulating BoNT. This is however ineffective once the toxin is internalised. Promising advances include monoclonal antibody therapies such as B8C1ad (Cyto-111), which in animal studies protects SNARE proteins intracellularly. Pyridostigmine (Mestinon), a reversible acetylcholinesterase inhibitor, is showing potential as a localised injectable reverser for iatrogenic BoNT-A effects such as eyelid ptosis. Topical adrenergic agonists, including apraclonidine and oxymetazoline, offer symptomatic relief in mild cases. Conclusion: BoNTs remain exceptionally safe when used by trained practitioners with approved formulations and dosages. Nonetheless, emerging antitoxin and antidote research, alongside vigilant regulatory oversight, is essential to ensure continued patient safety as global neuromodulator use expands.