Acceptability of medicines for children is a challenge, yet critical to ensure adherence to treatment. There is very little literature on formulation factors that influence acceptability of medicines, particularly in the domiciliary environment. This pragmatic study was conducted at University Hospital Coventry and Warwickshire (UHCW) with the aim of identifying the prevalence and nature of oral formulation-related barriers to medicines administration in children suffering from long-term conditions. This study used semi-structured face-to-face interviews with 221 parents/carers of children (0-18 years) and 57 young people (12-18 years). Result showed significant medicines refusal and manipulation in the domiciliary environment. Nearly one-third (71/232) of respondents reported medicines refusal. This was associated significantly with the age of child (p = 0.016), socioeconomic status (IMD 2010 score) (p = 0.002), taste (p < 0.001), texture (p = 0.017), and volume (of liquid/powder) or quantity (of solid dosage form) (p < 0.001). 29% (74/252) of respondents reported manipulating medicines. P-values are based on multivariable statistical analysis models. This study has indicated that formulations prescribed to children with chronic conditions are not meeting the needs of a significant number of patients based on self-report. Age-appropriate medicines are required to provide suitable dose units with an acceptable taste for children. This study should aid pharmaceutical companies to prioritise paediatric formulation work.