INTRODUCTION Smoking cessation has significant health benefits. The purpose of this study is to assess the efficacy and related factors of smoking cessation therapies in the Jazan Region of Saudi Arabia. METHODS This is a cross-sectional study that took place at smoking cessation clinics in primary healthcare centers between January 2019 and January 2020. RESULTS This study enrolled a total of 103 people. The success rate for quitting smoking was 36% at three months, with a 13% relapse rate at six months. Age (p=0.017), occupation (p=0.046), daily cigarette intake (p=0.015), and number of visits (p=0.001) were all found to be significant determinants of smoking cessation. In the multivariate analysis, only the number of visits increased the likelihood to quit smoking (AOR=0.31; 95% CI: 0.15–0.63). Self-efficacy was cited as the primary reason for quitting smoking by 71% of the participants, whereas family support, smoking cessation therapies, and friends’ support were cited as predictive variables by 18%, 10%, and 1% of the participants, respectively. CONCLUSIONS Smokers who received the smoking cessation intervention package were three times more likely to succeed in giving up smoking when compared to those who received the routine service. Regular follow-up during smoking cessation interventions significantly enhanced the quit rate. It is recommended that pharmacotherapy strategies and intense therapy performed face-to-face with a cessation counselor be combined to improve the quit rate.