Background. Transparent aligners are recently introduced orthodontic devices considered promising for the improvement of oral health conditions, in terms of faster treatment times and enhanced comfort, especially if compared with traditional fixed orthodontic therapy. This systematic review aimed to evaluate at-home protocols for proper oral hygiene and aligners cleaning during orthodontic treatment. Methods. A search was conducted using the following four databases: PubMed, Cochrane Library, Web of Science, and Scopus. The systematic review (registered as CRD 42024562215) followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and included prospective studies, randomized controlled trials (RCTs), controlled clinical trials, and in vivo and ex vivo studies; they had to assess treatment with invisible orthodontics compared to treatment with fixed orthodontics, home oral hygiene, or aligner disinfection protocols. The evidence in the studies was evaluated for risk of bias using the RoB-2 (for RCTs and randomized crossover studies) and ROBINS-I tools (for observational studies). Results. Eleven studies were included in this systematic review: four RCTs, four crossover studies, and three cross-sectional observational studies. Seven studies considered patients undergoing orthodontic treatment, whereas four examined orthodontic aligners. The cleaning protocols of the aligners were evaluated based on the analysis of residual biofilm on the thermoplastic surfaces. Studies included were characterized by a low level of certainty, thus further evidence is needed. Conclusions. The most effective protocols entailed a combination of mechanical and chemical agents, suggesting that it is fundamental for patients undergoing aligner treatment to focus on individually tailored home oral hygiene protocols.