Objective: To compare the effectiveness of a novel cetylpyridinium chloride (CPC)‐hyaluronic acid (HA)–based mouthrinse with chlorhexidine (CHX) and placebo mouthrinses in preventing plaque and gingivitis. The secondary outcomes were calculus, extrinsic stains, oral malodour and occurrence of adverse events. Methods: A 21‐day randomized, double‐blind, three‐arm parallel study with random allocation of young dental students to any of the three mouthrinse groups. Thorough prophylaxis was done at baseline followed by a baseline examination for oral malodour, extrinsic stains, calculus, gingivitis and plaque by a single examiner. All the subjects used the allocated mouthrinse twice daily for 21 days and were examined again at the end of the experimental period. They were also interviewed for adverse events. Change in the scores of clinical indices was calculated and compared between the groups. Results: A total of 75 subjects were included and completed the experiment. There was a significant difference for change in plaque index scores between the groups (P = .015); subjects in the placebo group experienced higher levels of plaque accumulation than the other groups. Teeth staining increased in the CHX (P < .001) and placebo groups (P = .002), but not in CPC‐HA users (P = .573). No significant differences were found between the three experimental groups for change in the gingival index (P = .08), calculus scores (P = .494), oral malodour (P = .870) and reporting of adverse events (P = .249). Conclusions: CPC‐HA and CHX had similar effectiveness in preventing plaque accumulation, while no differences were observed between the mouthrinses for preventing gingivitis. Dental staining was caused by CHX and the placebo mouthrinses but not by CPC‐HA mouthrinse.