Background <p>Diphtheria remains a major pediatric health threat in under-resourced settings, particularly in populations with low immunization coverage. Despite being vaccine-preventable, outbreaks continue to occur in Pakistan due to delayed recognition, limited access to diphtheria antitoxin (DAT), and weak public health infrastructure. Sindh province, including Sukkur and surrounding districts, has reported recurrent outbreaks in recent years, highlighting the urgent need for local data to guide management and prevention strategies.</p> Objective <p>To evaluate the clinical features, complications, and treatment outcomes of children diagnosed with diphtheria at a tertiary care hospital in Sukkur, Pakistan, and to identify predictors of mortality.</p> Methods <p>This retrospective cohort study was conducted from 1 September to 30 November 2024 at Children Hospital, Sukkur (SICHN). It included 45 children aged 0–15 years who met the World Health Organization (WHO) probable case definition for diphtheria. Data on demographics, clinical presentation, laboratory parameters, vaccination status, timing of antitoxin administration, complications, and outcomes were analyzed. Statistical tests included Chi-square, independent t-test, and binary logistic regression to identify independent predictors of mortality.</p> Results <p>Among 45 children, 53.3% were male, and 77.8% were under 10 years of age. The overall mortality rate was 42.2%. The most frequent clinical features were bull neck (82.2%), fever (75.6%), sore throat (75.6%), shortness of breath (66.7%), and pseudomembrane formation (62.2%). Major complications included respiratory failure (48.1%), myocarditis (20.4%), acute kidney injury (27.8%), neuropathy (16.7%), and bleeding (14.8%). Shortness of breath and pseudomembrane formation were significantly associated with mortality. On multivariable logistic regression, shortness of breath (Adjusted OR = 3.9, <i>p</i> = 0.02), pseudomembrane formation (Adjusted OR = 2.9, <i>p</i> = 0.04), and elevated serum creatinine (Adjusted OR = 4.8, <i>p</i> = 0.01) were independent predictors of mortality. Urea was associated with mortality in univariable analysis but was not significant in the multivariable model. Children receiving DAT after five days of illness had higher mortality (75%) and complication rates (77.8%) compared to those treated within three days. Only 22.2% of patients were fully vaccinated.</p> Conclusion <p>Shortness of breath, pseudomembrane formation, respiratory failure, and renal dysfunction were key predictors of poor prognosis in pediatric diphtheria. Early diphtheria antitoxin administration and complete vaccination are critical to improving survival. Strengthening surveillance systems, ensuring timely DAT availability, and enhancing vaccination coverage are essential to reduce morbidity and mortality in future diphtheria outbreaks.</p> Clinical trial number <p>Not applicable.</p>