Introduction: Open defaecation (OD) has been strongly linked to high prevalence of cholera and other sanitation-related diseases. This study was conducted to assess community-led total sanitation (CLTS) on the reduction of OD practices and its health implications in Cross River State. The study design was a community-based randomized controlled trial. Materials and Methods: A multi-stage sampling technique was used in selecting LGAs, wards, communities, households and respondents. Data were collected from 744 respondents at pre- and post-intervention. Data were analyzed using Statistical Product and Service Solution (version 24). Results and Discussions: Results were presented as frequencies, percentages, tables and charts. The findings from this study showed a significant increase in knowledge level of OD due to the CLTS intervention; at baseline, 344 (46.2%) of respondents had good knowledge of OD, which was later increased to 395 (53.1%) at post-intervention, indicating that there was a statistically significant difference in respondents’ knowledge level of OD and diseases associated with OD practices due to the CLTS intervention. The perceptions of respondents about OD were 404 (54.3%) at baseline, and was improved to 701 (94.2%) at post-intervention, implying that there was a statistically significant difference in the perceptions of respondents about OD practices due to the CLTS intervention. Conclusion: Based on the findings, the CLTS intervention was effective in increasing knowledge of OD practice, changing wrong perceptions about OD and improving toilet ownership and maintenance. To scale up the gains of this study, continued commitments to the eradication of OD practices from community members, governments at all levels and NGOs is crucial.