〔Abstract〕 Objective To investigate the effects ofTrpc6 knockout on chronic lipopolysaccharide (LPS)-induced myocardial inflammation and fibrosis in mice and its potential mechanisms. Methods Male C57BL/6 wild-type (WT) mice and Trpc6 knockout (Trpc6-/-) mice of the same background were randomly divided into four groups: WT control, WT+LPS (200 μg/kg), Trpc6-/- control, and Trpc6-/-+LPS (200 μg/kg). Group with LPS received intraperitoneal LPS injections for 21 consecutive days to induce chronic myocardial inflammatory injury. Cardiac ultrasound assessed changes in left ventricular ejection fraction (EF), left ventricular shortening fraction (FS), and cardiac output (CO). Hematoxylin and eosin (HE) staining and periodic acid-Schiff (PAS) staining were used to examine morphological alterations in myocardial tissue. Masson’s trichrome staining was used to assess myocardial fiber alterations; Western blot analysis was used to measure myocardial tissue expression of transient receptor potential calcium channel 6 (TRPC6), nucleotide-binding domain-containing receptor 3 inflammasome (NLRP3), interferon-induced molecule 2 inflammasome (AIM2), caspase-1, Interleukin-6 (IL-6), and Interleukin-1β (IL-1β) in mouse myocardial tissue. Results Compared with the WT control group, the WT+LPS group exhibited decreased cardiac EF (P < 0.01), FS (P < 0.01), and CO (P < 0.05), along with significantly increased myocardial tissue damage, glycoprotein deposition, and fibrosis (P < 0.01). Further analysis revealed that compared with the WT control group, the WT+LPS group exhibited markedly increased myocardial tissue expression of TRPC6, NLRP3, AIM2, Caspase-1, IL-6, and IL-1β (P < 0.01). Compared with the WT+LPS group, mice in the Trpc6-/- +LPS group exhibited elevated EF (P < 0.01) and FS (P < 0.05), along with reduced myocardial tissue injury, glycoprotein deposition, and fibrosis (P < 0.05). Conclusion Chronic LPS treatment can activate NLRP3/AIM2 inflammasomes through the up-regulation of TRPC6 expression, and then lead to chronic myocardial inflammatory injury and fibrosis, while Trpc6 knockdown can reduce myocardial inflammatory injury and fibrosis, and the mechanism is related to inhibiting the activation of NLRP3/AIM2 inflammasomes.