Pediatric patients are at increased risk of exposure to potentially harmful excipients when receiving off-label medicinal products primarily formulated for adults, raising concerns about adverse events. Based on data from a previously published study, this research focuses on the most frequently prescribed off-label medicinal products in order to assess the safety of their excipients. The aim was to identify Excipients of Mandatory Declaration (EMDs) that could pose additional safety risks in individuals under the age of 18. A descriptive, and retrospective observational population-based study in individuals under 18 was developed in the Spanish primary care setting between the years 2004–2005 and 2017–2020. The main data source was proprietary database, with nationwide coverage of prescriptions. The analysis included 4,922,984 off-label prescriptions, accounting for 16 active ingredients and 37 medicinal products (18 oral, 16 topical and three inhaled) that were scrutinized for EMD composition. Neonates and infants up to five years old accounted for nearly 50% of all off-label prescriptions among the under-18 population, exposing them to additional safety risks from potentially harmful EMDs in these formulations, which may lead to severe adverse events, causing permanent or long-term harm. The degree of harm of EMDs was assessed overall as “severe” for nine out of 22 EMDs, mostly used for oral formulations, and “moderate” for six EMDs. No EMDs were categorized as “no harm”. Results on EMDs in oral medicinal products, for instance, highlight the urgent unmet needs in this regard, especially for young children; EMDs like sodium, sorbitol, propylene glycol and sweeteners often exceeded EMA-recommended thresholds. This study underscores the need to address risks linked to off-label use of medicinal products in children, particularly those related to EMDs. Integrating excipient risk warnings into prescribing systems and monitoring related adverse events is strongly recommended.