Postpartum depression (PPD) is a serious public health problem in many Middle Eastern countries. Mothers with PPD experience various extreme symptoms that affect their daily lives. This study aims to discover how common PPD is in the Jazan region, the most significant risk factors, and how likely depressed women are to seek help. An observational cross-sectional survey targeting a sample of 444 mothers in their first year after delivery using a pre-tested and validated EDPS standard tool to evaluate the prevalence of postpartum depression amongst them has been conducted. The data was collected and then analyzed using SPSS. Descriptive statistics and inferential statistics were used for data analysis. Multivariate logistic regression was used to assess the risk factors associated with PPD. The results indicate an extremely high prevalence of PPD in Jazan (75.7%). The prevalence of mothers having suicidal ideation was 6.3% quite often, 5.0% sometimes, and 7.9% hardly. Regarding the duration of depression symptoms, 34.78% were less than a month, 20.72% were less than six months, and 13.06% were less than one year. The study shows that the development of depression symptoms occurred within less than a week for 30.4% of the women. The most significant association with PPD was a lack of family support, which significantly increased the risk of PPD (OR = 5.9; p-value < 0.001). The mothers who had unexpected pregnancies had a risk of PPD (OR = 2.5; p-value < 0.001). Current research has revealed a high prevalence of postpartum depression among mothers in the Jazan region and that it is associated with different risk factors that increase the probability of PPD development. Pregnant women need to raise their awareness about PPD and learn how to avoid or deal with it.