Soil phosphatase enzymes are produced by plant roots and microorganisms and play a key role in the cycling of phosphorus (P), an often-limiting element in terrestrial ecosystems. The production of these enzymes in soil is the most important biological strategy for acquiring phosphate ions from organic molecules. Previous works showed how soil potential phosphatase activity is mainly driven by climatic conditions and soil nitrogen (N) and carbon. Nonetheless, future trends of the activity of these enzymes under global change remain little known. We investigated the influence of some of the main drivers of change on soil phosphatase activity using a meta-analysis of results from 97 published studies. Our database included a compilation of N and P fertilization experiments, manipulation experiments with increased atmospheric CO2 concentration, warming, and drought, and studies comparing invaded and non-invaded ecosystems. Our results indicate that N fertilization leads to higher phosphatase activity, whereas P fertilization has the opposite effect. The rise of atmospheric CO2 levels or the arrival of invasive species also exhibits positive response ratios on the activity of soil phosphatases. However, the occurrence of recurrent drought episodes decreases the activity of soil phosphatases. Our analysis did not reveal statistically significant effects of warming on soil phosphatase activity. In general, soil enzymatic changes in the reviewed experiments depended on the initial nutrient and water status of the ecosystems. The observed patterns evidence that future soil phosphatase activity will not only depend on present-day soil conditions but also on potential compensations or amplifications among the different drivers of global change. The responses of soil phosphatases to the global change drivers reported in this study and the consideration of cost–benefit approaches based on the connection of the P and N cycle will be useful for a better estimation of phosphatase production in carbon (C)–N–P models.