BackgroundTotal work-family conflicts (TWFCs) could associate with mental health, and having ikigai (a purpose of life) may mediate this association.MethodsIn a cross-cultural study of 4,792 Japanese Aichi Workers’ Cohort study participants and 3,109 Egyptian civil workers, the Midlife Development in the United States (MIDUS) questionnaire measured TWFCs and the Center for Epidemiological Studies Depression (CES-D) 11-item scale measured depression. We used logistic regression models to estimate odds ratios (ORs) of having depression and a high-ikigai across levels of TWFCs (low, moderate, and high), and the PROCESS macro of Hayes to test the mediation effect.ResultsThe prevalence of high TWFCs, depression, and having a high ikigai were 17.9%, 39.4%, and 70.1% in Japanese women, 10.5%, 26.8%, and 70.1% in Japanese men, 23.7%, 58.2%, and 24.7% in Egyptian women, and 19.1%, 38.9%, and 36.9% in Egyptian men, respectively. Compared with participants with low TWFCs, the multivariable ORs of depression in Japanese women and men with high TWFCs were 4.11 (95% confidence interval [CI], 2.99–5.65) and 5.42 (95% CI, 4.18–7.02), and those in Egyptian women and men were 4.43 (95% CI, 3.30–5.95) and 4.79 (95% CI, 3.53–6.48), respectively. The respective ORs of having a high-ikigai were 0.46 (95% CI, 0.33–0.64) and 0.40 (95% CI, 0.31–0.52) in Japanese women and men and were 0.34 (95% CI, 0.24–0.48) and 0.28 (95% CI, 0.20–0.39) in Egyptian women and men. No interaction between TWFCs and country was observed for the associations with depression or ikigai. Ikigai mediated (up to 18%) the associations between the TWFCs and depression, especially in Egyptian civil workers.ConclusionTWFCs were associated with depression, and having low ikigai mediated these associations in Japanese and Egyptian civil workers.