Background <p>In recent years, Mycoplasma pneumoniae (MP) has developed widespread resistance to macrolide antibiotics, and second-line anti-Mycoplasma drugs such as levofloxacin have begun to be used in children. However, there is currently insufficient data on their efficacy and safety.</p> Objective <p>To explore the application effect of levofloxacin in children with refractory Mycoplasma pneumoniae pneumonia (RMPP) and evaluate its safety.</p> Methods <p>This study is an exploratory research, selecting 82 RMPP patients treated with levofloxacin who were admitted to the Department of Pediatric Respiratory Medicine at Weifang People’s Hospital between November 2023 and December 2024 as the research subjects. Compared the blood routine and biochemical indicators before and after the application of levofloxacin, and observed the clinical efficacy and adverse reactions of levofloxacin.</p> Results <p>The average fever reduction time after the application of levofloxacin was (1.96 ± 1.52) days. After the application of levofloxacin, there was no change in white blood cell (WBC), neutrophil (N), platelet (PLT) and other parameters in the blood routine (<i>P</i> &gt; 0.05). The lymphocyte count (L) has increased but remains within the normal range. There was no difference in alanine aminotransferase (ALT) before and after treatment, but aspartate aminotransferase (AST) decreased compared to before. Lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CKMB) decreased after medication (<i>P</i> &lt; 0.05), while creatine kinase (CK) remained unchanged. Blood creatinine (CREA) and Blood urea (Urea) both decreased (<i>P</i> &lt; 0.05), indicating no damage to liver and kidney function. There were a total of 9 adverse drug reactions related to levofloxacin, including 5 cases of rash, 2 cases of gastrointestinal reactions, 1 case of neurological reaction, and 1 case of lower limb pain. No other adverse reactions or sequelae were observed during the 12-month clinical follow-up.</p> Conclusion <p>Levofloxacin has shown good efficacy in treating RMPP in children, with no serious adverse reactions detected in a short period of time.</p>