Cardiovascular diseases are the main cause of mortality and disability worldwide. This study aimed to assess knowledge of cardiovascular disease and risk factors among the adult population in the south region of Saudi Arabia. A web-based cross-sectional survey of 1,049 participants was completed during August 2021. Data were collected by using 25-item heart disease fact questionnaire. The study population included 526 men (50.1%) and 523 women (49.9%) with a mean age of 36 ± 12 years. The average total knowledge score was 65.7 ± 20.80. The items with the highest knowledge were smoking, overweight, aging, high cholesterol, hypertension, diabetes, and family history. Findings revealed that knowledge regarding cardiovascular diseases is inadequate with a high prevalence of risk factors among the Saudi Arabian population. Healthcare professionals and organizations have a crucial role in raising public awareness regarding health promotion, regular screening, and lifestyles modifications. Interventional studies are needed to investigate the actual magnitude of CVDs and counteract them.