This study examined the mediating role of emotion regulation difficulties in the relationships of HEXACO personality traits, humor styles, and spitefulness with attitudes toward marital infidelity. A descriptive-correlational research design was employed using structural equation modeling with the partial least squares approach (PLS-SEM). The participants were 390 teachers from Qarchak County who were selected through multistage purposive sampling and completed the HEXACO Personality Inventory (Ashton & Lee), Difficulties in Emotion Regulation Scale (Gratz & Roemer), Humor Styles Questionnaire (Martin et al.), Spitefulness Scale (Marcus et al.), and Marital Infidelity Questionnaire (Yeniçeri & Kökdemir). Data were analyzed in R using the seminr package with 5,000 bootstrap resamples. The model explained 57% of the variance in emotion regulation difficulties and 31% of the variance in attitudes toward marital infidelity. Emotionality and spitefulness were positively associated with emotion regulation difficulties, whereas extraversion, agreeableness, conscientiousness, and affiliative humor were negatively associated with emotion regulation difficulties. Emotion regulation difficulties, spitefulness, and aggressive humor were positively associated with attitudes toward marital infidelity, whereas conscientiousness was negatively associated with such attitudes. Significant indirect effects were found for all six predictors; however, partial mediation was supported only for conscientiousness and spitefulness. These findings suggest that emotion regulation difficulties constitute an important but insufficient mechanism underlying attitudes toward marital infidelity. Accordingly, preventive interventions should address emotion regulation as well as attitudinal and relational factors, particularly spitefulness and aggressive humor.