As hybrid work arrangements have taken root in organizations in recent years, many individuals are spending a greater share of their time working from home (Bell, McAlpine, & Hill, 2023; Parker, 2023). Home-based workdays pose unique challenges, including greater chances for work to be interrupted by family members (what we call family-to-work interruptions; Leroy, Schmidt, & Madjar, 2021). Such cross-domain interruptions inherently involve a different relational context and set of demands than those stemming from the work domain, presenting unique challenges that are important to understand independent from work-to-work (intra-domain) interruptions. To advance our understanding of the affective consequences of cross-domain interruptions, we theoretically and empirically integrate the disparate research streams on intra- and cross-domain interruptions and address the limitations identified in prior work. Drawing on affective events theory (AET; Weiss & Cropanzano, 1996), we examine the effect of family-to-work interruptions on negative affect and, in turn, emotional exhaustion in a sample of 95 individuals (357 person-day observations) using experience sampling methodology. Further, we assess the role of individuals’ general perceptions of family-to-work conflict as a cross-level moderator of this effect. We find that family-to-work interruptions have unique effects on negative affect and emotional exhaustion over and above work-to-work interruptions, particularly for individuals with higher overall perceptions of family-to-work conflict.