Abstract Background There is a recent global surge in Mycoplasma pneumoniae pneumonia (MPP). However, the key immune factors that contribute to the advancement of the disease remain unknown. Hence, we conducted this study to uncover the immunological profile in children affected by MPP. Methods This study enrolled children visiting Children’s Hospital of Fudan University from December 2023 to April 2024, including 34 healthy controls, 51 severe MPP (S-MPP), 27 non-severe MPP (NS-MPP), and 34 non-MPP pneumonia (NMP) cases. Their blood samples were analyzed using flow cytometry, multi-cytokine assays, and antibody detection methods. Results Compared with NMP cases, MPP cases displayed higher frequencies of natural killer T cells, classical monocytes, and monocytic myeloid-derived suppressor cells. Notably, both T helper type 1 and activated regulatory T cells were more abundant in MPP cases, particularly in S-MPP, whereas CD8 + T cells displayed an exhaustion phenotype. The proportion of naïve B cells was reduced, while functional B cells, including memory B cells and plasmablasts, increased in S-MPP. 12 out of 95 clinical laboratory indicators and 3 out of 48 cytokines significantly differed between S-MPP and NS-MPP. Finally, we performed logistic and LASSO regression analyses and developed a predictive model for S-MPP that incorporates naïve B cell percentage from flow cytometry, cholinesterase from clinical laboratory tests, and interleukin 18 from the cytokine assay. Conclusions These results clarify the immunological features in pediatric MPP cases, and identify novel markers for severe cases, providing insights for early diagnosis and immunological management in affected children.