This study explored the current economic issues and isolated constraints involved in the spice business in Ondo State, Nigeria. A quantitative research approach was used to elicit information from 60 randomly selected respondents through an individual interview schedule with the aid of a well-structured questionnaire. Data collected was explored using descriptive statistics, and budgetary and multiple regression analyses. The results showed that most (57%) respondents were male, and 87% were married with a mean household size of 7. Most (77%) had at least a primary education, and all of them were members of an association with the majority (78%) engaged in cooperative marketing of spices. Also, of the four selected spices, Aframomum melegueta, Piper guineese, Monodora myristica, Sylopia acthipea, only Aframomum melegueta was cultivated, others were gathered from the wild. The prominent constraints identified were the inability to propagate Piper guineese, Monodora myristica, and Sylopia acthipea; the lack of technology to harvest and dry Sylopia acthipea to meet the standard of the buyers; and the lack of access to high-value markets. The rate of return on investment was 0.98, and the factors that determine the profitability of the spice business included the level of education, household size, labor and value addition. Research efforts should be focused on the propagation of P. guineese, M. myristica, S. acthipea, the technology for drying and harvesting of S. acthipea, and capacity building on value addition to increase business profitability.