Objective: Septic cardiomyopathy (SCM), as a complication of the septic process, severely affects the myocardial function of patients, but its pathogenesis remains unclear. The article aims to explore the mechanism of tripartite motif 10 (TRIM10) in rats with SCM and provide animal experimental basis for the treatment and prevention of SCM. Material and Methods: An SCM rat model was constructed by intraperitoneal injection of lipopolysaccharide (LPS). Sh-NC and sh-TRIM10 groups were injected with sh-NC and sh-TRIM10 in the tail vein for 3 consecutive days before SCM modeling. The expression of TRIM10 was detected by Western blot and reverse transcription-polymerase chain reaction analyses. Hematoxylin-eosin staining was performed to observe pathological changes in myocardium. Cardiomyocyte apoptosis was detected by flow cytometry. Serum levels of cardiac troponin I, myohemoglobin, creatine kinase-MB, interleukin-18 (IL-18), interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), superoxide dismutase, and glutathione peroxidase (GSH-Px) were detected by enzyme-linked immunosorbent assay. Apoptosis-related proteins and toll-like receptor 4 (TLR4)/nuclear transcription factor-kappa B (NF-kappa B) pathway-related proteins were explored by Western blot assay. Results: TRIM10 expression increased in the LPS group (P < 0.0001). Myocardial tissue injury in SCM rats was improved after TRIM10 reduction compared with that in the LPS group. Knockdown of TRIM10 decreased the levels of MDA (P < 0.01), IL-18 (P < 0.0001), IL-1 beta (P < 0.0001), and TNF-alpha (P < 0.0001) and increased the contents of SOD (P < 0.001) and GSH-Px (P < 0.001) compared with those in the LPS group. TRIM10 reduced the apoptosis of H9C2 cells (P < 0.0001). After TRIM10 interference, the expression of p-P65/P65 (P < 0.0001) and TLR4 (P < 0.0001) was decreased. Conclusion: TRIM10 knockdown can reduce inflammation, oxidative stress, and apoptosis in SCM rats and has a protective effect on cardiomyocytes, which may be attributed to the regulation of the TLR4/NF-kappa B pathway.