Mycoplasma pneumoniae (MPP) induced pneumonia is a common disease of children. Sinomenine (SIN) is an isoquinoline mainly sequestered from Sinomenium acutum. It is a promising drug for treating arthritis, lung, colon, liver and gastric cancer. Hence, the present study investigated the role and mechanism of SIN treatment in MPP induced pneumonia in experimental in-vivo mice model. The BALB/c male mice were separated into four groups (n = 6 mice/group): normal, MPP, MPP + SIN (20 mg/kg bw), and SIN (20 mg/kg bw) alone. Results were expressed as mean +/- SD. Data were analyzed using one way Analysis of Variance (ANOVA) with the Dunnett's post hoc test using SPSS v 18.0. P value < 0.05 was considered significant. The total protein, cell count, inflammatory cytokines, MP-IgM, Monocyte chemo attractant protein-1 (MCP-1), and MP-DNA were measured. The protein expressions of Bax/Bcl-2, ERK, JNK, NF-kappaB were analyzed and histopathology of lungs was examined. SIN treatment significantly (p < 0.05) reduced the total proteins, cell counts in BALF, inflammatory cytokines, MP-IgM, MCP-1, MP-DNA and reversed the histological alterations. SIN attenuated the apoptotic pathway through the modulation of Bax/Bcl-2 expression. SIN alleviated pulmonary inflammatory mediators and apoptosis in MPP-infected mice via suppression of ERK/JNK/NF-kappaB signaling. SIN administration diminished inflammation and lung fibrosis by inhibiting apoptosis in MPP mice. Hence, SIN is a potential natural protective remedy for MPP. CI - (c) 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.