One of the most significant lactic acid bacteria genera is Lactobacillus, which is known to generate compounds such as bacteriocins that can stop the growth of harmful bacteria. The current study investigated the protective and therapeutic effects of two novel probiotic strains, Lactobacillus brevis PQ214320, and Bacillus subtilis PQ198038, on parasitological, histopathological, and immunological responses in mice infected with Trichinella spiralis. A total of 120 mice were divided into six groups, including a positive control group (C) which was infected with Trichinella infection and not treated, mice treated orally with albendazole (ALB) at a dose of 5 mg/kg bw for 3 days after infection, and mice treated with probiotics (109 Colony-Forming Unit (CFU)/mL/animal, in 100 µL of Ringer's solution) either pre- and post-infection with L. brevis PQ214320 (LP) or B. subtilis PQ198038 (BSP), or only post-infection with L. brevis PQ214320 (L) and B. subtilis PQ198038 (BS). Infection was induced by oral inoculation of 400 T. spiralis larvae. Parasite burden and, histopathological, and immune responses were assessed at 5 and 19 days post-infection. The results showed that the LP group had significantly reduced adult worm and muscle larval counts compared with the positive control group. In contrast, BSP reduced the parasite burden, but to a lesser extent. The immune response was characterized by elevated levels of IL 12 and IFN-γ in the LP group at 5 days -post-infection (dpi), indicating a strong Th1 response, which declined but remained significantly higher than in the control infected group at 19 dpi. Serum IgG responses were higher in the LP group at 19 dpi, suggesting that a more robust adaptive immune response was triggered by L. brevis. Pre- and post-treatment with B. subtilis PQ198038 and L. brevis PQ214320 significantly improved the histopathological abnormalities and collagen deposition in the small intestinal and diaphragm muscular tissues caused Trichinella infection and restored claudin 1 content in the same tissues. These findings suggest that L. brevis PQ214320 offers a stronger protective effect against T. spiralis infection, potentially through enhanced immune modulation and parasite reduction, whereas B. subtilis PQ198038 provides beneficial but less potent responses. This study highlights the potential of novel probiotics strains as adjunct protective agents and therapies against T. spiralis infection.