Liver granuloma is a major pathogenic factor responsible for schistosomiasis, and no effective drugs or therapy methods to treat it have been found so far. Praziquantel (PZQ) has shown some anti-schistosomal effect, but little information is available about the effect of PZQ-prolonged administration on granuloma formation around schistosome eggs. Herein, we investigated the effect of PZQ on hepatic granuloma formation by treating the mice infected with Schistosoma japonicum using a long-term PZQ transdermal delivery. The results showed that the mean area of granulomas in the group treated with PZQ transdermal agent was (175.47 ± 116.73) × 10(3) μm(2) at the 49th day postinfection and (71.96 ± 45.99) × 10(3) μm(2) at the 56th day, while that in the control group was (304.51 ± 140.55) × 10(3) μm(2) and (526.44 ± 268.06) × 10(3) μm(2), respectively. The content of hydroxyproline in the livers of mice approached to the normal level on the 154th day in the treatment group, but it continued to increase from the 28th day to the 154th day after infection in the control group and nontreatment group. The ALT activity in serum of mice in the treatment group was also significantly lower than that in the control group (*P ≤ 0.05). Our results suggest that the long-term PZQ transdermal delivery is critical in the therapeutic approach to control the progress of hepatic schistosomiasis induced by egg granulomas.