Background: During the COVID-19 pandemic, hydroxychloroquine (HCQ) and ivermectin were widely used, sometimes in combination, despite limited regulatory approval. Concerns remain regarding their safety, particularly potential neurotoxic effects following prolonged or high-dose exposure.

Objective: This study evaluated the effects of hydroxychloroquine, ivermectin, and their co-administration on brain weight and histomorphology of Wistar rats.

Methods: Eighty-four adult Wistar rats were randomly assigned into seven groups (n = 12/group): control, hydroxychloroquine (two dose levels), ivermectin (two dose levels), and combined hydroxychloroquine–ivermectin (two dose levels). Drugs were administered orally for up to 28 days. Animals were sacrificed on treatment days 5, 14, and 28. Brain weights were recorded and histological assessment was performed using haematoxylin and eosin staining.

Results: No statistically significant differences were observed in brain weights across all treatment groups compared with controls. Histological examination revealed neuronal atrophy in rats administered low-dose hydroxychloroquine after 14 and 28 days. Acute neuronal necrosis and gliosis were observed in rats administered ivermectin at 0.2 mg/kg on day 5 only, with no observable lesions at later time points. Co-administration of hydroxychloroquine and ivermectin showed no observable histological alterations at any treatment duration.

Conclusion: Hydroxychloroquine administration beyond five days was associated with neuronal atrophy, while ivermectin within therapeutic doses showed minimal and transient histological effects. Co-administration of hydroxychloroquine and ivermectin was not associated with adverse brain histomorphology under the conditions of this study.