Meningoencephalitis (ME) is potentially fatal and is caused by a wide array of pathogens. Diagnostic and health-care access gaps prevent accurate estimation of the pathogen-specific burden in low-resource settings. We present pathogen-specific etiologies among patients hospitalized with ME in Karachi, Pakistan. We performed a retrospective hospital database evaluation of pathogen etiology and outcomes of community-acquired infectious ME at a single tertiary care center in Karachi, Pakistan. Annual rates of hospitalization (ARH) were calculated by adjusting for missed cases and are reported per 100,000 population. From May 2017 to April 2020, 522 episodes of infectious ME were identified in 514 patients. The overall ARH from ME was 5.7/100,000 population (95% CI, 5.1–6.1). Among children younger than 5 years, the ARH was 9.8/100,000 population (95% CI, 8.1–11.8). Unknown causes of ME resulted in the greatest burden, with an ARH of 1.9/100,000 population (95% CI, 1.7–2.2). Among known causes, the greatest burden of hospitalizations resulted from tuberculous ME (0.8/100,000; 95% CI, 0.6–0.97), followed by pneumococcal and enteroviral ME (both 0.6/100,000 population; 95% CI, 0.5–0.8). The burden of ME caused by pathogens preventable through vaccination or public health measures outweighed that of ME from other causes (P 5 0.0092, Fisher’s exact test). We report a broad range of pathogens causing ME in southern Pakistan and show a high burden of preventable illness. Synergistic actions to improve diagnostic strategies, increase vaccinations, and introduce measures to reduce water-borne and vector-borne diseases are required to reduce the ME burden in Pakistan and prevent future outbreaks.