Background Gastroesophageal reflux disease (GERD) is one of the most common gastrointestinal disorders that has substantial health and economic consequences. Several modifiable risk factors are associated with GERD, hence we conducted the present study to assess the prevalence and risk factors of GERD in a previously understudied population of southwestern Saudi Arabia. Methods A cross-sectional study was carried out to calculate the prevalence of GERD and assess its risk factors. A structured self-administered questionnaire was distributed on a random sample of 853 participants from Jazan region, Saudi Arabia. The questionnaire consisted of questions on the participants’ sociodemographic and lifestyle characteristics. The presence of GERD was detected using the GERD questionnaire (GerdQ). Data were analyzed using descriptive statistics and chi-square test, with a significance level of P < 0.05 or P < 0.01. Results The study included 853 participants; 69.1% males and 30.9% females. The proportion of participants who scored >8 on the GerdQ (had GERD) was 32.2%. GERD was associated with age (P < 0.01), marital status (P < 0.01), employment status (P < 0.01), fast food intake (P < 0.01), analgesics use (P < 0.01), and smoking (P < 0.01). GERD was more common among Khat chewers compared to non-Khat chewers (P < 0.05) and showed a significant association with the frequency of Khat use. Conclusion The results show a high prevalence of GERD in the general population of Southwestern Saudi Arabia. Several sociodemographic and lifestyle characteristics were associated with the disease.Copyright © 2020, Kariri et al.