Background/ Objectives: Pediatric palliative care aims to relieve suffering and improve the quality of life of children with serious conditions and their families. The aim of the study was to assess changes in quality of life following enrollment in a pediatric palliative care program at a tertiary care center in Mexico and to identify factors influencing these changes. Methods: This prospective cohort study included children with life-limiting or disabling conditions receiving care at a tertiary hospital in Mexico City. Quality of life was measured using the Pediatric Quality of Life Inventory Cancer Module for oncological patients and the Family Impact Module for all families at baseline, three months, and six months. Results: A total of 186 children were enrolled. While most had cancer, other diagnoses included neurological disorders and congenital anomalies. Mean child’s Quality of life scores improved from 58.9 to 77.9 (p < 0.001), and family scores from 60.1 to 78.8 (p < 0.001) over six months, with significant gains across emotional, physical, and relational domains. Families residing outside Mexico City had lower baseline scores but showed greater improvements. Families of children with non-cancer conditions experienced smaller gains. Median survival varied, with longer survival observed in children with neurological or intracranial conditions. Conclusions: Specialist pediatric palliative care improved the well-being of children and families in a middle-income setting. Equitable access should be ensured for families affected by chronic conditions, particularly those living beyond major urban areas.