Health-related Quality of Life (HRQoL) is a multi-faceted construct influenced by a myriad of environmental, demographic, and individual characteristics. Our understanding of these influencers remains highly limited in neurodevelopmental conditions. Existing research in this area is sparse, highly siloed by diagnosis labels, and focused on symptoms. This review synthesized the evidence in this area using a multi-dimensional model of HRQoL and trans-diagnostically across neurodevelopmental conditions. The systematic review, conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Checklist, was completed in June 2023 using Medline, PsycInfo, Embase, PubMed, and Cochrane Library. Our search revealed 78 studies that examined predictors of HRQoL in neurodevelopmental conditions. The majority of these studies focused on autism and ADHD with a paucity of literature in other conditions. Cross-diagnosis investigations were limited despite the fact that many of the examined predictors transcend diagnostic boundaries. Significant gaps were revealed in domains of biology/physiology, functioning, health perceptions, and environmental factors. Very preliminary evidence suggested potentially shared predictors of HRQoL across conditions including positive associations between HRQoL and adaptive functioning, male sex/gender, positive self-perception, physical activity, resources, and positive family context, and negative associations with diagnostic features and mental health symptoms. Studies of transdiagnostic predictors across neurodevelopmental conditions are critically needed to enable care models that address shared needs of neurodivergent individuals beyond diagnostic boundaries. Further understanding of HRQoL from the perspective of neurodivergent communities is a critical area of future work.