Informal caregivers of children with special healthcare needs (SHCN) are at risk for negative affect and poor quality of life (QOL). Inherent, or trait, mindfulness is thought to attenuate stress, depression, and anxiety (negative affect) and improve QOL. We aimed to investigate differences between caregiver groups (caregivers of children with and without SHCN), while exploring the effects of trait mindfulness on the relationship between caregiver group, QOL, and negative affect. A cross-sectional design was used with 120 informal caregivers of children with and without SHCN. Analysis included independent samples t-tests for between group differences and PROCESS Macro (Model 4) with 5000 bootstrapping was used to test the indirect effect of trait mindfulness on negative affect and QOL. Informal caregivers of children with SHCN had poorer negative affect, QOL, and lower levels of trait mindfulness than those caring for typically developing, healthy children. Trait mindfulness was found to significantly affect the relationship between caregiver group and QOL and partially accounted for the relation between caregiver group and negative affect individually in simple mediation models. Trait mindfulness may explain why some caregivers have higher levels of negative affect and worse QOL than others. Future research should explore the effects of severity of the child’s illness and caregiver gender on affect and QOL. Moreover, mindfulness in combination with other protective factors such as social support should be explored to gain a more complete understanding of how we can protect the wellbeing of those caring for vulnerable children.