Aquaculture represents the fastest growing food‐producing sector worldwide. However, the intensification of fish farms has led to environmental, health, and welfare challenges. The monogenean ectoparasite Gyrodactylus spp. has been considered one of the most pathogenic ectoparasites affecting fish, and no specific control strategies besides formalin baths have been established. The use of bioactive plants has been recently proposed as an alternative method to control gyrodactylid infections. Leucaena leucocephala is a tropical legume that has been found with anthelmintic activity against both internal and external parasites of cattle. Therefore, the objective of this study was to assess the anthelmintic‐like activity of L. leucocephala aqueous extract against Gyrodactylus spp. in hybrid tilapia Oreochromis spp. fingerlings and its effect on host health through histopathological analysis. Five concentrations of L. leucocephala aqueous extract were employed (2.00, 1.00, 0.50, 0.25, and 0.125 mg/mL) to estimate the mean effective concentration (EC50). Distilled water and formalin (1:4,000) were used as negative and positive controls, respectively. The aqueous extract of L. leucocephala showed a dose‐dependent behavior, with an EC50 of 0.228 mg/mL. Quercetin was identified as the main phytochemical present in the extract. Postmortem analysis of fingerlings exposed to the plant extract had no treatment‐associated pathological findings, thus indicating that the use of L. leucocephala baths had no negative impact that could jeopardize the lives of treated animals. After the in vivo assessment, the aqueous extract of L. leucocephala appears to be a promising alternative to control gyrodactylid infection in tilapia.