Background <p>Plaque control is essential for the prevention of dental caries and periodontal diseases. β-glycyrrhetinic acid (BGA) is an anti-inflammatory compound that has also been shown to be antibacterial. This study aimed to determine the effect of a dentifrice containing BGA on supragingival dental plaque accumulation.</p> Methods <p>Twenty-five patients who visited the Nagasaki University Hospital for periodontal maintenance from October 2020 to April 2022 were included in this study. It was a cross-over double-blind study, with BGA-containing and placebo toothpaste used for 1 week each. The use of toothpaste was randomly assigned using the block size 2 substitution block method. The primary endpoint was the area of plaque deposition on the margins after 1 week of toothpaste use for all teeth. The plaque deposition area was assessed using the Turesky–Gilmore–Glickmann Modification of the Quigley-Hein Plaque index (M-QHI) and statistically evaluated with a paired t-test.</p> Results <p>The plaque deposition area of all participants was analyzed after 1 week of use of BGA-containing and placebo toothpaste. The mean M-QHI after using the BGA-containing toothpaste was 0.63 ± 0.19, which was significantly lower (<i>p</i> &lt; 0.001) than the mean M-QHI after using the placebo toothpaste (0.75 ± 0.21). No significant adverse events were observed in any of the patients.</p> Conclusions <p>BGA-containing dentifrices may be useful in preventing caries and periodontal disease by inhibiting the accumulation of supragingival plaques.</p> Trial registration <p>This clinical trial was registered on UMIN-CTR (UMIN000040628, A verification study on plaque formation by using a dentifrice) on June 2, 2020.</p>