Background: Long-term follow-up studies establishing risk factors for loss of asthma control in well-controlled children with mild to moderate disease are lacking and are of importance for improving patient quality of life and utilization of health-care resources. Methods: Loss of asthma control was assessed in 146 school-aged children with well-controlled mild to moderate asthma from a Danish pediatric asthma outpatient clinic based on hospital admissions, emergency department (ED), or outpatient management of exacerbations, oral corticosteroid (OCS) use, or step-up of regular asthma treatment according to Global Initiative for Asthma (GINA) guidelines through a 5-year follow-up period. Risk factors included sex, ethnicity, age, body mass index (BMI), atopic comorbidity and predisposition, lung function, fractional exhaled nitric oxide (FeNO) level, exercise challenge test results, regular physical activity, GINA treatment step at baseline, and adherence to controller therapy. Results: A total of 27 (18%) children experienced 56 acute events defined by hospital admission, ED, or outpatient management. Risk of experiencing any acute event was increased with female sex (adjusted odds ratio, aOR = 2.4 (1.0–5.9), p = 0.047) and higher baseline GINA treatment step (aOR = 1.6 (1.1–2.5), p = 0.03). Furthermore, female sex (aOR = 6.1 (1.4–42.2), p = 0.01) and higher FeNO (aOR = 1.8 (1.0–3.2), p = 0.04) were associated with OCS prescriptions, whereas no risk factors were identified for GINA treatment step-up during the 5-year follow-up. Conclusions: Female sex, higher FeNO, and higher baseline GINA treatment step increase the risk of long-term loss of control including acute events and OCS use in well-controlled children with mild to moderate asthma. These findings are important for primary physicians and clinicians in asthma outpatient clinics to identify seemingly well-controlled children at risk to plan more frequent follow-ups.