Farming as a livelihood activity in the Bosomtwe District is threatened by climate change. This paper ascertained the alternative livelihood options of smallholder farmers against climate variability and change in the Bosomtwe District. Using a cross-sectional survey, 152 smallholder farmers were sampled from 12 communities using a multistage sampling procedure. The quantitative data collected were subjected to binary logistic regression analysis, contingency tables, frequencies, and Nagelkerke tests of association, embedded in the statistical package for social sciences (SPSS) v.17. The results indicate that farmers are resorting to alternative livelihood activities that are less capital intensive and require less skill in order to secure income and household food supply. Significant determinants of farmers' alternative livelihood are age, household size, and household food supply, which were significant at p < .030, p < .019, and p < .012, respectively. At a 95% confidence interval (CI), these variables had lower to upper CIs for each of the EXP (B), respectively, at CI = 1.134–12.524, CI = 1.359–30.224, and CI = 1.781–104.561, respectively. The paper recommends that government institutes policies that will create opportunities and draw on various local/grassroots opportunities and resources to expand farmers' asset base for sustainable livelihood strategies.