Long-term use of dopamine D₂ receptor blockers (D2RBs) often causes tardive dyskinesia (TD), an adverse symptom characterized by involuntary hyperkinetic movements. Despite extensive research, there is no effective strategy to reduce the risk of TD. One approach for finding potential treatments of a drug-induced adverse events is to analyse clinical big data by searching hidden drug-drug interaction. Here, we analysed FDA Adverse Event Reporting System and JMDC insurance claims to determine an effective drug that lowers the incidence of D2RB-induced TD, and we found that acetaminophen decreased the risk of drug-induced dyskinesia in both clinical datasets. Experimentally, 21-day oral treatments of rats with haloperidol increased the number of vacuous chewing movements (VCMs), a parameter of TD in rodents, and this effect was inhibited by oral administration of acetaminophen. In mice, haloperidol-induced VCMs were also mitigated by oral administration of acetaminophen or intrastriatal injection of AM404, an acetaminophen metabolite that acts as a TRPV1 activator. Finally, acetaminophen mitigated the haloperidol-induced decrease in the number of c-Fos/preproenkephalin double-positive indirect-pathway medium spiny neurons of striatum in wild-type mice but not in TRPV1-deficient mice. These results suggest a new treatment for TD with high clinical predictability and a well-defined molecular mechanism.