Post-COVID condition (PCC) in children and young people (CYP, PCCcyp) remains a significant health burden. Early identification of patients at risk for severe disease, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is crucial for timely and adequate care. This monocentric, observational registry study, performed at a tertiary pediatric hospital in Germany, included CYP aged 7–25 years with PCCcyp at diagnosis. Standardized clinical assessment tools and patient-reported outcome measures were applied, including the novel Munich Long COVID Symptom Questionnaire (MLCSQ). Severe PCC was defined by chronic symptom clusters, Fatigue Severity Scale (FSS), Total Composite Autonomic Symptom Score-31 (COMPASS-31), SF-36 composite scores, Bell Score, and confirmed ME/CFS diagnosis. Among 120 participants, severe PCCcyp was associated with a higher number of acute symptoms (OR_adj 1.22, P < 0.001), acute orthostatic intolerance (OR_adj 9.87, P = 0.002), acute trouble concentrating (OR_adj 11.8, P = 0.005), and female sex (OR 3.31, P = 0.031). Categorizing acute symptoms at a threshold of ≥ 12 yielded optimal model performance (AUC 0.857; sensitivity 65.6%; specificity 90.2%). ME/CFS was diagnosed in 24% of participants, all within the severe PCCcyp cluster, and was characterized by greater acute symptom complexity, more fatigue, more autonomic symptoms, and poorer function. Conclusions: The number and pattern of acute symptoms during SARS-CoV-2 infection may serve as early, specific predictors of severe PCCcyp. Patients with ≥ 12 acute symptoms should be closely monitored to enable early diagnosis of severe PCCcyp and ME/CFS. A distinct cluster of severely affected patients, frequently with ME/CFS, was identified. Trial registration: ClinicalTrials.gov: NCT05638724; Ethics approval (511/21, 2025–465-S-SB).