Background. Rheumatic fever (RF) is considered an inflammatory disease intermediated by an unusual immune reaction to group A streptococcal (GAS) infections that may lead to rheumatic heart disease (RHD). Patients with RHD have high mortality and morbidity rates despite being young. It was estimated that 3.49/per 1,000 RF patients had acute recurrent attacks yearly in middle and low-income countries. Examining the predictors of Saudi women's knowledge and attitude regarding RF and RHD is very important to help policymakers and healthcare providers address these predictors whilst raising public awareness regarding these important health issues. Thus, improving knowledge and attitudes may help in the early identification of symptoms, the application of effective treatment, an increase in prevention rates and a decrease in prevalence rates.Objectives. The study aimed to assess the knowledge and attitude about RF and RHD among mothers in Najran, Saudi Arabia. Material and methods. A descriptive cross-sectional design was used to recruit 389 participants in the maternity ad children's hospital in Najran, Saudi Arabia. The data was collected from November 2021 to March 2022 using a self-reported questionnaire for data collection; it consisted of study participants' basic data and health history, RF-and RHD-related knowledge quiz, and the RF and RHD treatment and preventive measures attitude scale. Results. The mean age of the participants was 30.59 years, although more than half (59.1%) of the participants had unsatisfactory knowledge concerning RF and RHD, and four-fifths (80.2%) of them had a positive attitude regarding its treatment and preventive measures. Satisfactory knowledge was statistically associated with mothers' education, age, history of a child with RDF and positive attitude toward preventive and treatment measures (p < 0.05). Conclusions. Unsatisfactory knowledge regarding RF and RHD was prevalent among the current study participants. At the same time, most had a positive attitude toward its treatment and preventive measures. Education level, mother's age, history of a child with RDF and positive attitude are significant positive predictors of RF and RHD knowledge.