Background: Depression occurs in one-third of stroke patients, in what is known as post-stroke depression. The lesion sites in stroke have been associated with the degree of depression. However, studies have provided different perspectives, and this necessitates further clarification. This study investigates the relationship between the lesion sites and the severity of depression in ischemic stroke patients. Methods: This cross-sectional study was conducted between January and April 2020. All samples were obtained from admitted patients with ischemic stroke who agreed to participate in the study. Data were collected using Beck’s Depression Inventory-II (BDI-II), which was used to determine the severity of depression, and the lesion sites were based on radiological imaging interpretation. Results: The study showed a significant association between the lesion site and the degree of depression (OR = 5,368, p-value = 0,013). Lesions in the frontal lobe demonstrated stronger associations with the severity of depression. Conclusion: The location of the lesion, especially in the frontal lobe, was associated with more severe post-stroke depression.