Objectives The current investigation was done with the aim of studying the mediating role of cognitive emotion regulation in the relation between brain-behavioral system activity and marital satisfaction of families living in Mahshar city. Methods 200 married people (106 female & 94 male) referring to two clinics of Petrochemical Industries of Mahshahr that were selected voluntarily. Research measurements were Gray-Wilson Personality Questionnaire (GWPQ), ENRICH Marital Satisfaction Scale (Persian-Brief), and the Cognitive Emotion Regulation Questionnaire (CERQ). Results The results showed that all dimensions of cognitive emotion regulation and brain-behavioral system activity of participants were significantly associated with marital satisfaction. The results also showed that both negative and positive strategies of cognitive emotion regulation and two dimensions of active avoidance and the fight/flight system as components of the behavioral-brain system activity directly and the behavioral inhibition system indirectly were associated with marital satisfaction. In general, the results of this study showed that the components of the brain-behavioral system and cognitive emotion regulation strategies have good predictive power to predict marital satisfaction in families. Conclusion The brain-behavioral system activity as a biological and sustainable model of personality and using the cognitive emotion regulation strategies has an essential role in predicting marital satisfaction - as a general outcome of long-term interactions between couples.