Alternative treatment modalities are being sought after reports of rising anthelminthic medication µresistance and their combination. This study looked at the helminthicidal and inhibitory effects of P. nitida extract on a few targets for metabolic enzymes in Fasciola gigantica. A complete Randomized Design (CRD) of 13 treatments duplicated three times with six adult F. gigantica in each replicate was used. Group A had no treatment (experimental control) and received no extracts at all. Mebendazole (Mevadex), 50 µg/mL, was administered to Group B-E as the standard control. The experimental groups F–I and J–M received treatments with water and methanol extracts of P. nitida leaf, respectively. Percentage mortality, motility, and impact of the extracts on some metabolic enzymes were assayed. At the third hour of exposure, all test groups' F. gigantica mortality levels significantly increased (p < 0.05) compared to the control. At 600 µg/mL concentration, the methanol fraction had a greatest death rate of 94.4% (n = 17) in 3 hours. In comparison to the control, there was a substantial drop in glycolytic enzymes (p < 0.05). Hexokinase (1.92 ± 0.09 U/g at 150 µg/ml), Pyruvate kinase (5.88 ± 0.91 U/g at 600 µg/ml), and Glucose Phosphate Isomerase (4.22 ± 0.68 U/g at 600 µg/ml) all showed greater effects in the aqueous fraction. The trend was independent of concentration. The decrease in the glycolytic enzyme levels suggests that P. nitida extract exhibited helminthicidal property by decreasing the liver fluke metabolic rate, offering a target for pharmacological intervention.