Local anesthetics (LAs) are widely used in anesthesia and pain medicine, offering effective analgesia for surgical and nonsurgical procedures. Although generally safe, systemic absorption or inadvertent intravascular injection may cause LA systemic toxicity (LAST), a potentially life-threatening emergency. LAST encompasses a range of neurologic and cardiovascular manifestations, from prodromal symptoms such as tinnitus and perioral numbness to seizures, arrhythmias, cardiovascular collapse, and cardiac arrest. Risk factors include high vascularity at the injection site, excessive dosing, inadvertent intravascular injection, extremes of age, underlying comorbidities, and continuous perineural catheter infusions. Bupivacaine is particularly cardiotoxic due to its high binding affinity and slow dissociation from cardiac sodium channels. Liposomal bupivacaine can potentially extend the duration of analgesia but carries unique safety considerations for patients who receive it and should not receive additional LAs for at least 96 h. Prevention hinges on dose vigilance, epinephrine test dosing in select cases, incremental injection, and ultrasound guidance. Management requires prompt cessation of LA administration, airway and circulatory support, seizure control, and early initiation of lipid emulsion therapy. Epinephrine should be used only in small doses, while vasopressin, calcium channel blockers, and beta-blockers should be avoided due to potential adverse interactions. Extracorporeal membrane oxygenation or cardiopulmonary bypass may be lifesaving in refractory cases. With prompt recognition and appropriate treatment, LAST has become a rare and largely survivable complication.