BACKGROUND: Cardiovascular disease (CVD) is the largest contributor to the non-communicable diseases (NCD) burden in Cameroon, but data on its economic burden is lacking. METHODS: A prevalence-based cost-of-illness study was conducted from a healthcare provider perspective and enrolled patients with ischaemic heart disease (IHD), ischaemic stroke, haemorrhagic stroke and hypertensive heart disease (HHD) from two major hospitals between 2013 and 2017. Determinants of cost were explored using multivariate generalized linear models. RESULTS: Overall, data from 850 patients: IHD (n = 92, 10.8%), ischaemic stroke (n = 317, 37.3%), haemorrhagic stroke (n = 193, 22.7%) and HHD (n = 248, 29.2%) were analysed. The total cost for these CVDs was XAF 676,694,000 (~US$ 1,224,918). The average annual direct medical costs of care per patient were XAF 1,395,200 (US$ 2400) for IHD, XAF 932,700 (US$ 1600) for ischaemic stroke, XAF 815,400 (US$ 1400) for haemorrhagic stroke, and XAF 384,300 (US$ 700) for HHD. In the fully adjusted models, apart from history of CVD event (β = - 0.429; 95% confidence interval - 0.705, - 0.153) that predicted lower costs in patients with IHD, having of diabetes mellitus predicted higher costs in patients with IHD (β = 0.435; 0.098, 0.772), ischaemic stroke (β = 0.188; 0.052, 0.324) and HHD (β = 0.229; 0.080, 0.378). CONCLUSIONS: This study reveals substantial economic burden due to CVD in Cameroon. Diabetes mellitus was a consistent driver of elevated costs across the CVDs. There is urgent need to invest in cost-effective primary prevention strategies in order to reduce the incidence of CVD and consequent economic burden on a health system already laden with the impact of communicable diseases.