Background: Neuromuscular blocking agents (NMBAs) are essential in modern anesthesia, but inadequate reversal leads to residual neuromuscular blockade (RNMB), causing significant postoperative complications. This study compares the efficacy, safety, and clinical outcomes of neostigmine and sugammadex for reversal of neuromuscular blockade. Methods: A comprehensive review of randomized controlled trials and observational studies comparing neostigmine and sugammadex was conducted. Primary outcomes included time to reversal, incidence of RNMB, and postoperative complications. Secondary outcomes examined hemodynamic stability, adverse effects, and cost-effectiveness. Results: Sugammadex demonstrated significantly faster reversal times across all depths of blockade compared to neostigmine. The incidence of RNMB was markedly lower with sugammadex (2-5%) versus neostigmine (15-40%). Sugammadex showed superior safety profile with fewer cardiovascular and muscarinic side effects. Conclusions: Sugammadex offers superior efficacy and safety compared to neostigmine for reversal of neuromuscular blockade, particularly in deep blockade scenarios. Despite higher acquisition costs, improved outcomes and reduced complications support its clinical adoption.