Depression has a significant role in the overall world disability, and populations who are under constant psychosocial stress are more vulnerable. Nigeria’s strong pro-natalist norms create a strong value for fertility which makes childlessness an important area of psychological distress. There is a high prevalence of infertility depression among childless couples of the South Western Nigeria, but there has not been a study of the role that life satisfaction plays in depressive outcome in this group. This study was based on uncovering the association between life satisfaction and depression in childless married persons, whether higher life satisfaction possessed a protective outcome against depression. A cross-sectional survey was undertaken among 200 purposively sampled married couples, without a child, from Oyo, Ogun, and Lagos states. The participants complete a questionnaire containing demographic profile, Beck Depression Inventory-II (BDI-II) and the Satisfaction with Life Scale (SWLS) scales. The data was analysed using descriptive statistics, Pearson’s correlation, chi-square and simple linear regression at a significance level of p < .05. Results demonstrated that a significant number of proportions of the participants (58.0%) reported clinically significant depressive symptoms (BDI-II ? 20). Pearson’s correlation demonstrated that there was a strong negative correlation between life satisfaction and depression, r(198) = –.62, p < .001. Moreso, the results of the regression analysis demonstrated that life satisfaction predicted significantly levels of depressive symptoms, B = –0.72, ? = –.62, t = –11.70, p < .001; and explaining 40.7% of the variance in depressive symptoms; R² = .407.The results identify life satisfaction as a primary protective factor against depression among childless married people in Southwestern Nigeria, it was suggested that enhancing life satisfaction through culturally sensitive interventions may serve as an effective approach to reducing depressive symptoms in this population.