The Universe's early thermal history is poorly constrained, and it is possible that it underwent a period of early matter domination driven by a heavy particle or an oscillating scalar field that decayed into radiation before the onset of Big Bang nucleosynthesis. The entropy sourced by this particle's decay reduces the cross section required for thermal-relic dark matter to achieve the observed abundance. This degeneracy between dark matter properties and the thermal history vastly widens the field of viable dark matter candidates, undermining efforts to constrain dark matter's identity. Fortunately, an early matter-dominated era also amplifies density fluctuations at small scales and leads to early microhalo formation, boosting the dark matter annihilation rate and bringing smaller cross sections into the view of existing indirect-detection probes. Employing several recently developed models of microhalo formation and evolution, we develop a procedure to derive indirectdetection constraints on dark matter annihilation in cosmologies with early matter domination. This procedure properly accounts for the unique morphology of microhalo-dominated signals. While constraints depend on dark matter's free-streaming scale, the microhalos make it possible to obtain upper bounds as small as σv < ∼ 10 −32 cm 3 s −1 using Fermi-LAT observations of the isotropic gamma-ray background and the Draco dwarf galaxy.