AbstractSoil enzymes are crucial in mediating ecosystems' responses to environmental drivers, so that the comprehension of their sensitivity to drivers of global change can help make predictions of future scenarios and design tailored interventions of biomanipulation. Drivers of global change usually act in combination of two or more, and indirect effects of one driver acting through modification of another one often occur, yet most of both manipulative and meta‐analysis studies available tend to focus on the direct effect of one single driver on the activity of specific soil enzymes. One of the biggest challenges is, therefore, represented by the difficulty in assessing the interactions between different drivers, due to the complexity of disentangling the single direct effects from the indirect and combined ones. In this review, after elucidating the general mechanisms of soil enzyme production and activity regulation, we display the state‐of‐the‐art knowledge on direct, indirect and combined effects of the main drivers of global change on soil enzyme activities, identify gaps in knowledge and challenges from research, plus we analyse how this can reverberate in the future of biomanipulation techniques for the improvement of ecosystem services. We conclude that qualitative but not quantitative outcomes can be predicted for some interactions such as warming + drought or warming + CO2, while for other ones, the results are controversial: future basic research will have to center on this holistic approach. A general trend toward the overall increase of soil enzyme activities and acceleration of biogeochemical cycles will persist, until an inflection will be caused by factors such as future shifts in microbial communities and changes in carbon use efficiency. Applied research will develop toward the refinement of “in situ” analytical systems for the study of soil enzyme activities and the support of bioengineering for the better tailoring of interventions of biomanipulation.