It is known that excretory/secretory antigens of Fasciola hepatica (ESFh) trigger a Th2-like immune response. Anapsos® (A) is an aqueous hydrosoluble extract obtained from the rhizomes of the fern Polypodium leucotomos that has shown immunomodulator effects in some parasitic infections and immunological disorders. In this work we assess the effect of Anapsos® and ESFh and Quillaja saponaria extract (Qs) on BALB/c mice and rat alveolar macrophages. Anapsos® modulates the response of mice immunized with ESFh, decreasing IgG1 antibodies in A ESFh− and A Qs ESFh−treated mice and triggering high levels of γIFN in spleen cell culture in comparison with ESFh− and Qs ESFh−treated groups. Moreover, Anapsos® showed statistically significant inhibitory effects on the nitrite production by rat alveolar macrophages prestimulated with lipopolysaccharide (LPS) as well as ESFh antigen in comparison with macrophages stimulated only with LPS. The application of ESFh and Anapsos® combined avoids this inhibitory effect. Thus, Anapsos® modulates the immune response against ESFh in naive mice and on the nitrite production in prestimulated rat alveolar macrophages.