Worldwide, stroke is the second leading cause of death and a frequent cause of permanent disability. The objective was to identify the first-time stroke modifiable risk factors in the Aseer region, southwest Saudi Arabia. In a multicenter hospital-based case-control study design, all first stroke patients admitted to hospitals in the Aseer region were included consecutively over one year. Age, sex, and geographical residence-matched controls were selected and included in a ratio of 1:1. Data collected included altitude (low or high), nationality, marital status, educational level, family history of stroke, history of diabetes mellitus, history of systemic hypertension, high cholesterol level, current smoking, obesity, and regular exercise practice. The study included 1249 first-time stroke patients and 1249 age, sex, and residence-matched controls. Hypertension, diabetes mellitus, obesity, and high cholesterol were significantly highly prevalent among cases (57.7%, 49.4%, 42.0%, 29.4%, respectively) compared to controls (31.8%, 25.9%, 30.8%, 12.1%, respectively). Practicing regular exercise was significantly highly prevalent among controls (29.9%) compared to cases (13.1%). Multivariable logistic regression analysis revealed that systemic hypertension (adjusted odds ratio (aOR) = 2.12, 95%CI: 1.74–2.57), diabetes mellitus (aOR = 1.73, 95%CI: 1.41–2.21), obesity (aOR = 1.95, 95%CI: 1.61–2.28) and high cholesterol (aOR = 1.64, 95%CI: 1.28–2.10) were significant risk factors, while regular exercise practice was a significant protective factor (aOR = 0.12, 95%CI: 0.05–0.26) for stroke. Hypertension, diabetes mellitus, obesity, and high cholesterol are major risk factors for stroke in the Aseer region of southwest Saudi Arabia. The protective role of regular physical activity in reducing the risk of stroke is evident. The observed higher prevalence of potentially modifiable risk factors among stroke cases encourages an urgent need to develop and implement a national program to control these factors.