(1) Objectives: Studies on mpox patterns, severity predictors, and public health impacts in Burundi remain limited. Therefore, we aimed to identify the clinical predictors and determinants of mpox complications among hospitalized patients in Bujumbura, Burundi, during an active outbreak. (2) Methods: We conducted a prospective cohort study of laboratory-confirmed mpox cases across three treatment centers (July-October 2024). Clinical characteristics and outcomes were assessed through a systematic review of medical and laboratory records supplemented by structured interviews with patients or caregivers. Risk factors for disease complications were evaluated using multivariate Firth penalized logistic regression. (3) Results: Complications developed in 3.1% of 850 patients (54.4% male; median age, 20.3 years). Conjunctivitis (odds ratio [OR]: 27.30; 95% confidence interval [CI], 7.67-122.23) and sore throat (OR: 12.63; 95% CI, 5.78-30.21) were significant predictors of severe disease progression. Conversely, generalized rash (OR, 0.10; 95% CI, 0.04-0.24) and lymphadenopathy (OR, 0.24; 95% CI, 0.08-0.62) were associated with a mild disease course. Sexual transmission was the predominant route of infection (58.6%). (4) Conclusions: Noncutaneous manifestations, particularly conjunctivitis and sore throat, are early indicators of mpox severity. These findings inform clinical risk stratification in resource-limited settings and highlight the need for further investigation of pathophysiological mechanisms.