Daily affect is important to health and has been linked to cortisol. The combination of high negative affect and low positive affect may have a bigger impact on increasing HPA axis activity than either positive or negative affect alone. Financial strain may both dampen positive affect as well as increase negative affect, and thus provides an excellent context for understanding the associations between daily affect and cortisol. Using random effects mixed modeling with maximum likelihood estimation, we examined the relationship between self-reported financial strain and estimated mean daily cortisol level (latent cortisol variable), based on six salivary cortisol assessments throughout the day, and whether this relationship was mediated by greater daily negative to positive affect index measured concurrently in a sample of 776 Coronary Artery Risk Development in Young Adults (CARDIA) Study participants. The analysis revealed that while no total direct effect existed for financial strain on cortisol, there was a significant indirect effect of high negative affect to low positive affect, linking financial strain to elevated cortisol. In this sample, the effects of financial strain on cortisol through either positive affect or negative affect alone were not significant. A combined affect index may be a more sensitive and powerful measure than either negative or positive affect alone, tapping the burden of chronic financial strain, and its effects on biology.