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Background: Mozambique is one of the countries in Africa that is continuously at risk of cholera outbreaks due to poor sanitation, hygiene, and limited access to potable water in some districts. The Mozambique Cholera Prevention and Surveillance (MOCA) project was implemented in Cuamba District, Niassa Province to prevent and control cholera outbreaks through a preemptive cholera vaccination, strengthened surveillance system for cholera and diarrheal diseases, and better understanding of cholera-related healthcare seeking behavior of local populations, which may further guide the national cholera control and prevention strategies. This article presents the surveillance component of the MOCA project. Methodology/Principal findings: A prospective healthcare facility (HCF)-based surveillance of cholera and diarrheal disease was conducted in six HCFs in the District of Cuamba from March 2019 to December 2020. A systematic surveillance procedure has been put in place with capacity building in selected sentinel HCFs and a basic microbiology laboratory established on-site. Patients presenting with suspected cholera or other diarrheal symptoms were eligible for enrollment. Clinical data and rectal swab samples were collected for laboratory confirmation of Vibrio Cholerae and other pathogens. A total of 419 eligible patients from six HCFs were enrolled. The median age was 19.8 years with a similar age distribution between sentinel sites. The majority were patients who exhibited diarrhea symptoms not suspected of cholera (88.8%; n = 410). Among those, 59.2% (210/397) were female and 59.9% (235/392) were 15 years and above. There were 2 cholera cases, coming outside of the catchment area. The incidence of diarrheal diseases ranged from 40–103 per 100,000 population. No Vibrio cholerae was isolated among surveillance catchment population and Escherichia coli spp. (82/277; 29.6%) was the most common pathogen isolated. Conclusion/Significance: Efforts were made to strengthen the systematic surveillance of suspected cholera with standardised patient screening, enrolment, and diagnostics. The first basic microbiology laboratory in Niassa Province established in Cuamba District under the MOCA project needs to be integrated into the national network of laboratories for sustainability. No reports of laboratory confirmed cholera cases from the surveillance catchment area may be highly related to the pre-emptive oral cholera vaccine (OCV) mass vaccination campaign conducted in 2018 and the use of drugs by local populations prior to visiting the sentinel HCFs. Continued systematic cholera surveillance is needed to closely monitor the cholera endemicity and epidemics, and further evaluate the long-term impact of this vaccination. High incidence of diarrheal illnesses needs to be addressed with improved water, sanitation, and hygiene (WaSH) conditions in Cuamba District. Efforts integrated with the prioritization of prevention measures are fundamental for the control of cholera in the country. Author summary: Mozambique faces an ongoing risk of cholera outbreaks, due to factors such as poor sanitation and limited access to clean and potable water. To address this challenge, the Mozambique Cholera Prevention and Surveillance (MOCA) project was launched in one of the high-risk areas, Cuamba District, Niassa Province, in 2018. This initiative was an integral part of Mozambique's efforts to develop a comprehensive National Cholera Plan, aiming to bolster cholera and diarrheal disease surveillance and inform national prevention strategies. Under the MOCA project, we conducted a preemptive oral cholera vaccine (OCV) mass vaccination campaign in 2018 and implemented a healthcare facility-based surveillance for cholera and diarrheal diseases in six healthcare facilities in Cuamba District. A systematic cholera surveillance system was put in place in the study sentinel sites with standardised patient screening, enrolment, and diagnostic procedures. The first basic microbiology laboratory in Niassa province was established in Cuamba District in 2018 with funding and technical support made available under this MOCA project. A significant portion of patients in our surveillance system exhibited diarrheal symptoms unrelated to cholera, with a notable representation of females and individuals aged 15 years and older during the surveillance period in 2019–2020. No suspected cholera patients enrolled was laboratory-confirmed with Vibrio cholerae, which may be highly related to the cholera vaccination campaign performed in 2018 and the local populations' tendency on the use of drugs before seeking healthcare at the HCFs. Continued surveillance is recommended to track cholera endemicity and outbreaks and also to assess the long-term impact of OCV vaccination in Cuamba District. Better infrastructure and practice of WaSH is needed to reduce the high incidence of diarrheal illnesses in the local populations. Sustainable technical and financial support is needed in the rural remote areas of Cuamba District for the continued systematic cholera and infectious disease surveillance system, including laboratory confirmation. Integrating these efforts with preventive measures is crucial for effective cholera control in Mozambique. [ABSTRACT FROM AUTHOR]