There are large yield gaps in the mixed smallholder farming systems of Africa, with limited opportunities to sustainably increase productivity and adapt to climate change. In this study, the ex-ante potential of residue retention and fertilization measures to meet this challenge is assessed using a positive mathematical programming (PMP) model. This micro-economic model captures decision making at the farm level for a sample population in Northern Burkina Faso for the 2010 to 2045 simulation period. In contrast to previous studies of mixed farms in this area, we model each individual farm in the sample population, instead of one or a small number of representative farms. We are therefore able identify groups of farms for which each measure is profitable, applied either individually or as a combined package. This approach also enables simulation of the economic impacts from indiscriminate applications of the measures or “smart” applications which are restricted to the farms that profit from the measures. Our findings are aligned with other studies showing that residue retention causes trade-offs between crop and livestock production, while fertilization can synergistically raise returns to both production activities. The annual profit losses from the “middle of the road” RCP6 trajectory of climate change assumed in this study were estimated to reach 15% by 2045. The smart package of measures increased aggregate profit the most, although not by nearly enough to claw back the losses from climate change. The fertilizer measures were the next most profitable, with indiscriminately applied residue retention being the only measure to reduce aggregate profit relative to this climate change baseline. Importantly, the measures that are the most profitable at the aggregate level are not necessarily those that would be the most widely adopted. For example, residue retention is profitable for a larger share of the sample population than fertilization. The advantage of the population scale analysis used in this study is that it prevents measures such as residue retention, which can benefit a significant share of farms, from being disregarded by practitioners because they appear to be unprofitable at the aggregate level or when viewed through the lens of an average representative farm. Finally, amidst the growing emphasis of studies on the benefits of packages compared to individual measures, the findings from this study are more equivocal about this choice, suggesting that extension programs should have the flexibility to apply measures individually or as a package.