The antimalarial drug mefloquine (Mef) has shown an evident antischistosomicidal activity. The most preferable way of drug administration is through the oral route through which the total absorption of the drug is limited due to enzymatic degradation and the physiological barrier PH. Thus, the current investigation was conducted to assess the potential impact of Mef and chitosan nanoparticles (CS-NPs), which is known for its importance as a drug delivery structure, on the histological variations of liver that induced in mice infected with Schistosoma mansoni. Fifty-six mice were grouped into seven separate collections with eight mice in each group; G1 (positive non-treated control mice). At the 7th day post infection (PI), the groups were divided as follows: G2 (Mef dosage 400 mg/kg), G3 (CS-NPs dosage 500 mg/kg), G4 (Mef dosage 400 mg/kg with CS-NPs dosage 500 mg/kg). At the 21st day PI, the groups from G5-G7 were treated with the same previous doses respectively. The whole animals were managed to be sacrificed on the 56th day PI. Treatment with 400 mg/kg Mef at days 7 and 21 PI has reduced the granuloma diameter by 24.85% and 69.65% respectively, while Mef loaded to CS-NPs at days 7 and 21 PI showed a reduction in granuloma diameter by 57.18% and 100% respectively. Meanwhile, Mef loaded to CS-NPs treatment has reduced the number of granulomas in the liver. In conclusion, treatment of Mef loaded to CS-NPs is more effective than free Mef especially when administered 21 days PI.