Secretory Otitis Media (SOM) is a non-suppurative inflammatory disease of the middle ear. Saikosaponin D (SSD), a compound with significant anti-inflammatory and immunomodulatory properties, was investigated for its preventive effects and underlying mechanisms against SOM. A rat model of SOM was established through intraperitoneal ovalbumin injection. Middle ear lavage fluid (MELF) and tissue samples were collected for comprehensive analysis, including bacterial load quantification, neutrophil enumeration, and inflammatory factor assessment. HEK293T cells were utilized for mechanistic validation. Our findings demonstrated that SSD preventive treatment significantly reduced colony-forming units (CFUs) in SOM-induced rats, attenuated middle ear mucosal thickening, and suppressed pro-inflammatory cytokine levels (TNF-α, IL-6, and INF-γ). Mechanistically, SSD treatment counteracted SOM-induced mA level elevation and reversed the downregulation of FTO expression. Functional studies revealed that FTO inhibition exacerbated inflammatory responses, while SSD treatment mitigated these effects. Further investigation demonstrated that SSD decreased TLR4 mRNA stability through FTO-mediated mA modification. In conclusion, SSD alleviates SOM progression by reducing bacterial load and neutrophil infiltration. The therapeutic effects are mediated through FTO upregulation and subsequent mA-dependent TLR4 mRNA degradation. This study elucidates a novel molecular mechanism underlying SSD's preventive action against SOM development.