The possibility of using pozzolanic materials as a partial substitute for Portland cement (PC) to develop mortars and concretes promotes environmental and economic benefits. The present paper includes an in-depth investigation into the characterization of natural pozzolans from Guatemala for the valorization of these materials. An exhaustive physico-chemical characterization of the starting materials was first carried out. Second, an analysis of the pozzolanic reactivity of both pozzolans was performed using an evolution test of the pH and electrical conductivity measurements and a Frattini test. Finally, pastes and mortars were manufactured with pozzolans T and R as a substitute for PC. The results of the pH and electrical conductivity measurements confirmed that natural pozzolans can be classified as low-reactivity. The Frattini test and the thermogravimetric analysis confirmed the pozzolanic behavior of natural pozzolans at 28 curing days. In the cement pastes, lime fixation was positive for a long curing period, which demonstrated that these pozzolans had medium–long-term pozzolanic activity, similar to fly ash (FA). The results were confirmed by mechanical assays. The mortars with 15%, 25%, and 35% substitutions of cement for pozzolans had strength gain percentages of around 13–15% at 90 curing days.