Rational drug use can make important contributions to the treatment of diseases. Many factors affect rational drug use. This research was undertaken with the aim of defining the mediating role of health perception (HP) in the effect of e-health literacy (eHL) on rational drug use (RDU). The research presented here was performed between March 11 and April 29, 2023, in the Istanbul and Kocaeli provinces and their districts in Türkiye. Data were collected from individuals residing in Istanbul and Kocaeli provinces or in their districts aged 18 and over by online survey method. A total of 520 questionnaires were collected in this process. The findings revealed that eHL positively affects HP. Moreover, eHL and HP positively affect RDU. Finally, it was determined that HP has a mediating role in the effect of eHL on RDU. The research presented here has confirmed that eHL and HP are determinants of RDU. According to these results, some suggestions are presented.