Cocoyam belongs to the indispensable food category that supplies calorie in the diet of the Nigerian populace. However, researches on its nutrition and economic values are scarce leading to low production and under consumption among the populace. Against the backdrop of the great potential of the Nigerian agriculture in cocoyam production, and the need for land use efficiency, sustainable development, poverty alleviation, attainment of food –security/ self-sufficiency and adequate resource allocation to the production of the crop, this study examined farm level profit efficiency and its determinants for smallholder cocoyam-based farmers in Osun State, South-west Nigeria, using Cobb-Douglas stochastic profit function. Multistage and random sampling techniques were used to select 180 small-holder cocoyam farmers during the 2014 growing season and data were collected from them on their socio-economic and production characteristics. Maximum likelihood estimates of the specified models revealed an average profit efficiency of 44.88 percent which indicated that the profit of the farmers can be increased by 55 percent with the same production cost. The study also found that the level of education of the farmers, access to credit, farming experience, household size, access to extension services, and marital status are factors affecting farm-level profit efficiency in the use of resources. Farm-level policies aimed at promoting the farmers education, access to credit, access to extension services and marital status are recommended for improved profit efficiency.