Background: Drug-induced liver injury (DILI) is a significant cause of acute liver failure, with paracetamol (APAP) being a common culprit. This systematic review aimed to explore the risk factors associated with DILI following the therapeutic use of APAP in patients with genetic disorders. Methods: The protocol was registered with PROSPERO (CRD42023397546). Inclusion criteria encompassed studies reporting on DILI following the therapeutic use of APAP in patients with genetic disorders. A systematic search of EMBASE, PubMed, CINAHL, PsycInfo, grey literature databases, and search engines yielded 13 eligible case reports. Quality and risk of bias were assessed according to established guidelines. Results were synthesized both qualitatively and quantitatively. Results: Despite therapeutic dosing, high serum APAP levels and elevated liver function test values were observed which significantly correlated with APAP doses. Genetic polymorphisms in drug-metabolizing enzymes, glutathione deficiency, reduced volume of distribution, and other factors such as concomitant drugs, malnutrition, stress, dehydration, and genetic predispositions may have contributed. Delays in suspecting APAP toxicity and initiating N-acetylcysteine therapy were observed, contributing to severe liver injury. Conclusions: Understanding the determinants of DILI in this unique population is crucial to prevent medication errors and enhance patient safety. This study emphasises the need for personalised medicine and pharmacogenetic screening to identify susceptible individuals and guide APAP usage. It underscores the importance of raising awareness, vigilance, using lower doses, therapeutic drug monitoring, and proactive measures for early intervention. Dosage guidelines need to be revised. The main limitation of this study was the bias inherent in case reports.