We propose that the COVID-19 pandemic and the restrictions to daily life that followed had greater negative impact on the mental health, as measured by psychological distress, of employed parents than nonparents, because of an associated increase in both directions of work-family conflict and work-family guilt among this group of the population. To test this argument, we examined pooled data from two cross-sectional online surveys administered to heterosexual adults in dual-earning relationships living in the United States. The first data set was collected before the onset of the COVID-19 pandemic (N = 616), and the second data set was collected during the early months of the pandemic (N = 454). Results of multivariate analyses show that distress increased between the two surveys, but only among parents, as compared with nonparents, irrespective of gender of the respondent, or age of the youngest child. This association is due to a change in work-family conflict and guilt between the two surveys: among parents, the COVID-19 onset was associated with higher family-to-work conflict, work-to-family guilt, and family-to-work guilt; among nonparents the pandemic was associated with lower work-to-family conflict and work-to-family guilt. Our results suggest that the COVID-19 onset had contrasting effects on the lives of employed parents and nonparents.