Background: There has been a documented increase in the numbers of filial and sandwiched caregivers in the United States. However, past studies have overlooked the impact of work and family overload on caregiver well-being. Methods: This study investigates the moderating influences of the quality and directionality of work and family spillover on the well-being (e.g., positive affect and negative affect, psychological well-being, and global well-being) of 180 filial and sandwiched caregivers from the second wave of the Midlife in the United States Survey. Results: Regression and moderation analyses revealed that sandwiched caregivers with high levels of negative work-to-family spillover exhibited higher negative affect than the comparison groups. Sandwiched caregivers with high levels of negative family-to-work spillover exhibited higher level of negative affect and lower level of self-acceptance than other caregivers. Conclusions: These findings can help create work programs that address spillover between work and home in the effort to promote caregiver well-being.