Simple SummaryThis study assessed sleep problems, distress, and quality of life in parents of children with the most common form of childhood cancer, acute lymphoblastic leukemia (ALL). Parents completed questionnaires at different time points, shortly after diagnosis until 1 year after end of treatment. Before this study, longitudinal research on parental psychosocial functioning, especially sleep problems, was sparse. This study shows that although parental functioning improves over time, 33% of parents still report sleep problems three years after their child’s diagnosis. Half of those parents also report clinical distress. Presence of sleep problems and distress negatively affects quality of life over time. Vulnerable parents are those who experience little social support or parenting problems, report a chronic illness for themselves or pain for their child, have a child with higher risk ALL, and are closer to diagnosis. This study stresses the importance of systematically monitoring parental functioning both throughout and after treatment—including sleep.This study assessed sleep, distress and quality of life (QoL) in parents of children with acute lymphoblastic leukemia (ALL) from diagnosis to three years after, and the impact of sleep and distress on QoL. Additionally, this study explored determinants of sleep and distress. Parents completed the MOS Sleep, Distress Thermometer for Parents and SF-12 at four-five months (T0), one year (T1), two years (T2), and three years (T3) after diagnosis. The course of outcomes and longitudinal impact of clinically relevant sleep problems (>1SD above reference’s mean) and clinical distress (score ≥ 4) on QoL Z-scores were assessed with linear mixed-models. Determinants of sleep and distress were assessed with multinomial mixed-models. Parents (81% mothers) of 139 patients (60% males; 76% medium-risk (MR)) participated. Distress and QoL gradually restored from T0 to T3. Sleep problems improved, but were still elevated at T3: 33% reported clinically relevant sleep problems, of which 48% in concurrence with distress. Over time, presence of sleep problems or distress led to lower mental QoL Z-scores (SD-score −0.2 and −0.5, respectively). Presence of both led to a cumulatively lower Z-score (SD-score −1.3). Parents in the latter group were more likely to report insufficient social support, parenting problems, a chronic illness, pain for their child, having a child with MR-ALL, and being closer to diagnosis. In conclusion, parental well-being improves over time, yet sleep problems persist. In combination with ongoing distress, they cumulatively affect QoL. Special attention should be given to parents who are vulnerable to worse outcomes.