Background: Valproic acid (VPA) is a widely used anti-epileptic and mood-stabilizing drug, primarily metabolized by glucuronosyltransferases (UGT) and cytochrome P450 (CYP) enzymes. Few drug interactions are known to affect VPA levels, including carbamazepine, phenytoin, and carbapenems. We report a new drug that interacts with VPA: flucloxacillin. Case Presentation: A 79-year-old male with bipolar disorder, treated with VPA, presented with low VPA serum levels during treatment for S. aureus bacteraemia with flucloxacillin. His VPA levels decreased rapidly, despite no apparent explanation. Serial assessments ruled out nonadherence and absorption issues. Flucloxacillin was identified as the probable cause, as VPA levels normalized upon its cessation and dropped again with reintroduction. Discussion: This case illustrates a significant drug-drug interaction between flucloxacillin and VPA, likely mediated by induction of UGT enzymes rather than CYP enzymes. The rapid onset and resolution of the interaction suggest UGT induction as the primary mechanism. Probably, patients with a low albumin are more susceptible to this interaction, like our patient, due to increased metabolism. Conclusion: Flucloxacillin treatment substantially decreases total VPA serum levels while free fraction levels can be still within reference values. Clinicians should consider monitoring free fraction and adjusting dosages accordingly in bipolar disorder. If VPA is used for epilepsy, alternative antibiotics to flucloxacillin should be preferred.