This study aimed to evaluate alternative in vivo treatment trials using natural products for ectoparasitic infestation on Nile tilapia; these two products were not previously used in the treatment of parasitic fish diseases. So, a total of 400 Oreochromis niloticus (O. niloticus) fish measured 10-15 cm in length; 350 from a fish farm in (Kafr Elsheikh and 50 from Nile River (Al Bahr Al Aazam), Egypt. The examined fishes were 10-15 ± 0.5 cm long and weighed from 45 g ± 5. The collected fish were examined for different clinical abnormalities. Each part of the fish underwent a careful microscopic examination of mucous surrounding the skin; gills and fins. Two feed supplements were used experimentally to decrease mortality and treat fish against ectoparasites (Herb-All PARA-X® and Herb-All CALM®). Total mRNA was extracted from the gills of different examined groups. Glucose; nitric oxide; cortisol as well as lysozyme activity were assessed in all groups. The gills of the examined fish were collected for histopathological examination. Only, Dactyolgyrus sp. was recovered. The intensity of the parasite was counted per microscopic field. The treated groups showed low levels of the parameters compared to the control positive group. Up-regulation of both Tumor necrosis factor-α (TNF- α) and heat shock protein 70 (hsp-70) were detected in fins, gills, and skin in the infested tilapia. The treatment and prophylaxis significantly downregulated both genes in the studied organ in a dose-dependent manner. Recorded lesions which were scored according to their severity. In conclusion; following the use of those products, fish health has been greatly improved and that is indicated by findings of immune reactions as well as histopathology.