Background: To date, no study has compared the clinical characteristics of Mycoplasma pneumoniae-associated segmental/lobar pneumonia, Mycoplasma bronchopneumonia, and COVID-19 pneumonia primarily caused by the NB.1.8.1 variant in children. Methods: We examined the epidemiologic trends of pneumonia, segmental/lobar pneumonia, and COVID-19 pneumonia at a teaching hospital from 2015 to 2025. In addition, we compared the clinical characteristics of children hospitalized with Mycoplasma segmental/lobar pneumonia, Mycoplasma bronchopneumonia, and COVID-19 pneumonia during the NB.1.8.1 variant wave in 2024–2025. Results: Between 2015 and 2024, 10,601 pneumonia cases were identified, including 525 cases of segmental/lobar pneumonia and 162 cases of COVID-19 pneumonia. An outbreak of segmental/lobar M. pneumoniae pneumonia and COVID-19 pneumonia occurred in Taiwan during 2024–2025. Starting in early 2025, monthly Mycoplasma positivity rates among children with segmental/lobar pneumonia and bronchopneumonia exceeded 60%. Mycoplasma pneumonia predominantly affected children aged 6–11 years, whereas COVID-19 pneumonia mainly occurred in those younger than 3 years of age. Fever, cough, and rhinorrhea were the most common symptoms in all groups, limiting clinical differentiation. Children with segmental/lobar Mycoplasma pneumonia were more likely to present with prolonged fever (>5 days), lymphocytopenia, a neutrophil-to-lymphocyte ratio (NLR) ≥ 3, and elevated C-reactive protein (CRP) levels, each of which was strongly associated with macrolide non-response (all p < 0.001). Conclusions: Children with segmental/lobar Mycoplasma pneumonia demonstrated more severe clinical manifestations. Segmental/lobar involvement and inflammatory markers, such as lymphocytopenia, elevated NLR, and increased CRP levels, were associated with macrolide non-response. These indicators may help guide therapeutic decision-making in pediatric M. pneumoniae pneumonia.