Trichinella spiralis is a parasitic nematode with a special life cycle. Both adults and larvae live in two different niches in the same host (intestinal and muscular). The parasite is known to manipulate the immune system of the host to be able to survive. One of the pathways the parasite modulates is the programmed death 1/ programmed death ligand 1 (PD1/PDL1), a pathway important to maintain the immune homeostasis during chronic infections and cancers. Albendazole (ABZ) shows anti-trichinellosis efficacy, especially against the intestinal phase of the infection. In an attempt to discover a drug that would enhance the efficacy of ABZ against the muscular phase, we used 40 CD1 Swiss-Albino male mice divided into 5 groups: normal, infected, infected ABZ-treated, infected Silymarin (SM)-treated, and the infected-treated with a combination group. After euthanasia, the number of diaphragmatic larvae was estimated in the infected and the infected-treated groups. In addition, the tongues and hearts of all mice were subjected to histopathological and immunohistochemical processing and evaluation. Monotherapy groups showed a significant reduction of both larval count and PD1 local expression compared to the infected-only group, however, neither ABZ nor SM alone could reduce the inflammation accompanying infection. The most significant improvements were recorded in the combined treatment group with a reduction rate of 69.95%, a significant reduction of inflammatory infiltrates (p < 0.05), and significant modulation of PDL1 local expression (p < 0.05). So, Silibinin (the major active ingredient of SM) showed anti-trichinellosis activity and enhanced the efficacy of ABZ against the muscular phase of the infection.