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Abstract Background In October 2021, a large outbreak of cholera was declared in Cameroon, disproportionately affecting the Southwest region, one of 10 administrative regions in the country. In this region, the cases were concentrated in three major cities where a humanitarian crisis had concomitantly led to an influx of internally displaced persons. Meanwhile, across the border, Nigeria was facing an unprecedented cholera outbreak. In this paper, we describe the spread of cholera in the region and analyse associated factors. Methods We analysed surveillance data collected in the form of a line list between October 2021 and July 2022. In a case-control study, we assessed factors associated with cholera, with specific interest in the association between overcrowding (defined by the number of household members) and cholera. Results Between October 15, 2021 and July 21, 2022, 6,023 cases (median age 27 years, IQR 18–40, 54% male) and 93 deaths (case fatality 1.54%) were recorded in the region. In total 5,344 (89%) cases were reported from 6 mainland health districts (attack rate 0.47%), 679 (11%) from 4 maritime health districts (attack rate 0.32%). More than 80% of cases were recorded in 3 of 10 health districts: Limbe, Buea, and Tiko. The first cases originated from maritime health districts along the Nigeria-Cameroon border, and spread progressively in-country over time, with an exponential rise in number of cases in mainland health districts following pipe-borne water interruptions. Case fatality was higher in maritime health districts (3.39%) compared to mainland districts (1.5%, p 5 people: (crude OR 1.73, 95% CI 0.97–3.12) and 3–5 people: (crude OR 1.47, 95% CI 0.85–2.60)), even after adjusting for internally displaced status and number of household compartments in the multivariable model (aOR 1.54, 95% CI 0.80–3.02). Conclusions We report the largest cholera outbreak in the Southwest region. Our findings suggest the cross-border spread of cases from the Nigerian outbreak, likely driven by overcrowding in major cities. Our study highlights the need for cross-border surveillance, especially during humanitarian crises.