Recently, research in the field of caries prevention is emphasizing upon identification of edible non-toxic compounds that can interfere with the formation of cariogenic biofilm. This trial aimed to assess the effectiveness of non-dialyzable material (NDM) containing cranberry mouth rinse (C-MR) on the Streptococcus mutans (S. mutans) counts and compare with that of a sodium fluoride (F-MR) mouth rinse. 280 children (8-12years old) were enrolled in this double-blind single center, parallel, one-month, IRB/IEC approved non-inferiority trial. The participants fulfilling the inclusion criteria were randomly allocated into one of the two groups: C-MR and F-MR. All participants were given verbal and written instructions about at-home mouth-rinsing regimen under parental supervision for a month. Dental plaque samples were collected before and after a month of mouth-rinsing and subjected to culture techniques. S. mutans counts were assessed and compared in both groups. Primary outcome was the difference in the S. mutans counts between two interventions. Both intention-to-treat (ITT) and per-protocol analysis were carried out using two-sample t test with equal variance. The mean S. mutans counts (after log transformation) in C-MR group were: 14.66 (90% CI 14.4,14.9) at baseline and 12.85 (90% CI 12.5, 13.2) colony-forming units/ml (CFU/ml) at one-month post intervention (p = 0.001); while these counts were 14.69 (90% CI 14.5, 14.9) at baseline and 12.71 (90% CI 12.3, 13.1) at one-month intervention in F-MR groups (p = 0.001). ITT analysis showed an inter- group difference of 0.14CFU/ml (90% CI -0.32,0.59) in post-SM counts between groups (p = 0.629). The study demonstrated that the cranberry mouth rinse was non-inferior to the fluoride mouth rinse in terms of S. mutans levels change. Cranberry-based mouth rinse can be used effectively to reduce the S. mutans counts in children. Registration number in case of Clinical Trials-CTRI/2019/05/019395.