Trichinosis is a real threat to public health that infects humans and animals. Current treatments have high resistance and limited bioavailability. Consequently, it is imperative to enhance the bioavailability of these drugs by developing new agents. So, the purpose of this study was to assess the efficacy of ivermectin-loaded chitosan nanoparticles (CS NPs) and their combination with albendazole (ABZ) on the muscular and intestinal phases of trichinosis. We had eight main groups of mice: non-infected control; infected control; infected and treated with ABZ; infected and treated with ivermectin (IVM); infected and treated with CS NPs; infected and treated with ABZ and IVM; infected and treated with IVM-loaded CS NPS; and infected and treated with ABZ combined with IVM-loaded CS NPS. Two subgroups were formed for each group: a and b for both phases, intestinal and muscular, respectively. Drug efficacy was parasitologically, histopathologically, serologically, and molecularly evaluated. The ABZ combined with IVM-loaded CS NPS-treated group showed the highest statistically significant reduction in adult and encysted larval counts and a noticeable reduction of both intestinal and muscular inflammation. In the treated groups, there was a significant decrease in TNF-α, iNOS, and IFN-γ gene expression when compared with the infected control. Although the level of IL10 was increased in all treated groups. In conclusion, IVM-loaded CS NPS enhanced the efficacy of ABZ against T. spiralis-infected mice.