Background and Objectives The mental and physical functioning of an individual is partly determined by their health-related quality of life (HRQOL), which is a multifaceted component. Women who have recently given birth must have a good quality of life to provide proper care and development for their infant. The purpose of this study was to assess the relationship between postpartum depression (PPD) and HRQOL in Saudi Arabian women and to identify potential risk factors that could influence them. Methods This study comprised 253 mothers aged 1–24 weeks postpartum from several health centers in Saudi Arabia, recruited by random purposive sampling. The study’s questionnaire featured three sections: the first section had demographic information; the second and third sections contained the Edinburgh Postnatal Depression Scale (EPDS) scale and the HRQOL scale (SF-12), respectively. Data were analyzed using descriptive statistics, chi square analyses, independent samples t-tests and binary logistic regression analysis using IBM SPSS 25. Results Results of current study indicate that 59.68% of the patients exhibited probable post-partum depression symptoms. Participants who were depressed had significantly lower mental component (MCS) and physical component scores than participants who were in good health. When compared to non-smokers, smokers have a 21-fold higher risk of developing depression. Similar to this, mothers who worked had a 3.98 times higher risk of depression, and patients with a history of depression had a 3.6 times higher chance of getting PPD. The probability of developing PPD was also significantly higher in those who lived outside the Riyadh region, had given birth more than twice before this time, and had experienced undesired pregnancies. Conclusion Our study demonstrated an inverse correlation between postpartum depression and health-related quality of life scores. Treatment for depression, particularly among mothers, is crucial for improving their quality of life and, as a result, creating a favorable environment for the development of newborn babies.