Introduction During 2023–2024, the Americas faced its largest dengue epidemic to date. We used a detailed dengue classification to identify patients with serious manifestations of dengue and aimed to describe risk factors for occurrence. Methods From April 2023 to September 2024, we conducted a prospective in-hospital active case-finding cohort study at the Hospital Universitario del Valle (HUV) in Colombia, enrolling patients of all ages with virologically confirmed dengue (VCD). Sociodemographic and clinical data were collected, and the dengue virus (DENV) genome was sequenced for serotyping and genotyping. Multivariable logistic regression modeling identified factors associated with “serious manifestations of dengue”, defined as severe dengue (2009 WHO classification) or dengue with warning signs (DwWS) with a more severe course, including vascular leakage (increases in hematocrit >20%, pleural effusion or ascites with hemodynamic/respiratory compromise); bleeding with hemodynamic instability or requiring blood transfusion; thrombocytopenia <20,000 or organ dysfunction (myocarditis, encephalitis or liver failure). Results Among 600 patients (median age 13 years, 55% male), serotyping and genotyping were possible for 340 (57%) and 296 (49%) samples, respectively. The most frequent serotypes were DENV-2 (32%) and DENV-3 (15%), and lineages 2II_F.1.1.2 (19%) and 3III_C.1 (15%). Serious manifestation of dengue occurred in 167 (28%) patients, including 22 with severe dengue and 145 DwWS cases with a more severe course. Independent risk factors for serious manifestations of dengue were living outside of city limits, presenting with edema and higher leukocyte counts, whereas lower odds were observed for patients with higher platelets and lymphocyte counts, and infections other than DENV-2. History of dengue infection showed no significant effect on the risk of serious clinical manifestations across the different serotypes. Conclusion This outbreak involved multiple dengue virus serotypes and genotypes and predominantly affected children and adolescents. Identification of the risk factors described here could enable earlier recognition of patients with serious dengue manifestations. In this cohort, serotype 2 was associated with higher risk but given the unpredictable dynamics of severe dengue, efforts should strive for tetravalent protection, regardless of prior dengue exposure.