Objectives To compare efficacy of aloe vera and probiotic mouthwashes vs fluoride mouthwash on Streptococcus mutans (S. mutans) in the plaque of orthodontic patients and to assess patient-reported outcomes and compliance. Materials and Methods This prospective randomized clinical trial included 90 patients aged 12–35 years and in permanent dentition, who were randomly allocated in a 1:1:1 ratio to three mouthwash groups: aloe vera, probiotic, or fluoride. Smartphone-based applications were used to improve patient compliance. The primary outcome was the change in S. mutans levels in plaque between two times: pre-intervention and after 30 days using real-time polymerase chain reaction (Q-PCR). Secondary outcomes were the evaluation of patient-reported outcomes and compliance. Results Mean differences between aloe vera vs probiotic: −0.53 (95% CI: −3.57 to 2.51), aloe vera vs fluoride: −1.99 (95% CI, −4.8 to 0.82), and probiotic vs fluoride: −1.46 (95% CI: −4.74 to 1.82) were not significant, P = .467. Intragroup comparison demonstrated a significant mean difference in all three groups of −0.67 (95% CI: −0.79 to −0.55), −1.27 (95% CI: −1.57 to −0.97), and −2.23 (95% CI: −2.44 to −2.00) respectively, P < .001. Adherence was above 95% in all groups. No significant differences in frequency of responses to patient-reported outcomes were found among groups. Conclusions No significant difference in efficacy among the three mouthwashes in reducing S. mutans level in plaque was found. Patient-reported assessments concerning burning sensation, taste, and tooth staining found no significant differences among mouthwashes. Smartphone-based applications can help improve patient compliance.