Informal caregivers (ICs) of cancer patients play a crucial role in health care. Several of the challenges they face can affect their quality of life (QoL). This cross-sectional study explored role of burnout and caregiving satisfaction in their relationship to QoL. Portuguese ICs of adult cancer patients (N = 92) answered a sociodemographic and caregiving questionnaire, the WHOQOL-SRPB BREF, assessing physical, psychological, social, environmental, and spiritual QoL domains; the Maslach Burnout Interview, assessing the dimensions of depersonalization, emotional exhaustion, and personal accomplishment; and a Visual Analogic Scale on caregiving satisfaction. We tested correlations and a parallel mediation model for each domain of QoL, considering burnout dimensions as possible mediators between satisfaction and QoL domains. Our results show that satisfaction, burnout dimensions, and almost all QoL domains are correlated. Together, burnout dimensions seem to mediate the relationship between caregiving satisfaction and psychological, environmental, and spiritual QoL. Satisfaction had a significant indirect effect solely through emotional exhaustion on psychological QoL (β = 1.615, 95% BCI [0.590; 2.849]), environmental QoL (β = 0.904, 95% BCI [0.164; 1.876]), and spiritual QoL (β = 0.816, 95% BCI [0.019; 1.792]). It seems essential for mental health professionals to address these dimensions when providing support to an IC.