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<div><p>Tomato spotted wilt orthotospovirus (TSWV) is one of the most destructive pathogens and causes serious losses in agriculture worldwide. Biogenic pesticides application may be an effective approach for defending against TSWV. Tagitinin A (Tag A) extracted from <i>Tithonia diversifolia</i> (Hemsl.) A. Gray has a high protective effect against TSWV infection. Tag A can induce jasmonic acid to suppress gene expression in TSWV. In this study, the F-box protein (CPR30) was mediated by Tag A, the expression of the <i>CPR30</i> gene in Tag A-treated leaves was significantly higher (2 times) than that of the negative control. Furthermore, the replication of TSWV-<i>NSm/NSs</i> genes and the expression of TSWV-NSm/NSs proteins significantly increased after silencing the <i>CPR30</i> gene in protective assays; <i>CPR30</i> overexpression showed the opposite tendency. The CPR30 protein only localized and interacted with the TSWV-NSm protein. Thus, this study reveals a new mechanism by which Tag A mediates ubiquitin–protein ligase E3 (CPR30) to interact with NSm inhibite NSm replication and expression, and defend against systemic TSWV infection.</p></div>