Hypertension, trouble sleeping and depression, as three major public health problems, were closely related. This study evaluated the independent association of trouble sleeping and depression with hypertension and interaction effect between trouble sleeping and depression on hypertension in Americans.The data of this cross-sectional study was from the 2005-2018 National Health and Nutritional Examination Survey (NHANES) with hypertension, depression, trouble sleeping and confounding factor information. Multivariate logistic regression model and subgroup analyses of depression severity were conducted to assess the relationship between trouble sleeping and depression on hypertension. Relative excess risk due to interaction (RERI), attributable proportion of interaction (AP) and synergy index (S) were utilized to assess the additive interaction.A total of 30,434 participants (weighted n = 185,309,883) were examined with 16,304 (49.37%) known hypertensive subjects. Compared with participants without trouble sleeping, those with trouble sleeping had a higher risk of hypertension [OR = 1.359 (95% CI: 1.229-1.503)]. We also found the significant association of depression with an increased risk of hypertension [OR = 1.276 (95% CI: 1.114-1.462)], compared with those without depression. Moreover, there was a significant interaction between trouble sleeping and depression on hypertension risk [RERI = 0.528 (95% CI: 0.182-0.873), AP = 0.302 (95% CI: 0.140-0.465), S = 3.413 (95% CI: 1.301-8.951)].There was a synergistic interaction between trouble sleeping and depression on hypertension, especially the significant synergistic effect between moderate depression and trouble sleeping on hypertension. The results suggested that improving the psychological status and trouble sleeping of patients may be beneficial to the prevention and treatment of hypertension.© 2022. The Author(s).