Hyaluronic acid (HA) has anti-inflammatory and anti-edematous effects and, thus, could be promising in the treatment of oral lichen planus (OLP). The aim of the study was to evaluate the effects of topical hyaluronic acid, compared to placebo, on salivary levels of calprotectin, interleukin-6 (IL-6), and bacteria, as well as clinical and subjective parameters. Fourteen patients with confirmed OLP were included. After random selection, patients started with either 0.2% hyaluronic acid or a placebo gel for 6 weeks. Following a wash-out period, the groups changed the application. Whole saliva, clinical parameters, and questionnaires were evaluated before and after the intervention, as well as after the crossover phase. Salivary calprotectin, IL-6, and inflammation-related bacteria were determined by ELISA and PCR, respectively. There were no significant differences in clinical or subjective outcome parameters, salivary levels of IL-6, calprotectin, or bacteria after the application of hyaluronic acid, compared to placebo. However, only nine patients completed the study, as five out of seven patients starting with placebo were lost to follow-up. Significant effects of HA on inflammatory mediators and clinical parameters in OLP patients could not be proven, although a trend in clinical severity improvement could be observed.