Hygroscopicity is an important factor affecting the physical stability of amorphous solid dispersions (ASDs) during long-term storage. In this work, the effects of temperature, relative humidity (RH), and polymeric excipients on the phase behavior of amorphous irbesartan (IRB) and oxaprozin (OXA) were systematically investigated. The ASDs were prepared by the solvent evaporation method. The water sorption in formulations was measured under the conditions of 25 °C, 60% RH, 25 °C, 90% RH, and 40 °C, 75% RH. The results showed that the hygroscopicity of formulations containing polyvinylpyrrolidone (PVP) was stronger than that containing poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA 46) and the hygroscopicity increased with increasing temperature and RH. With increasing content of active pharmaceutical ingredients (APIs), the recrystallization phenomenon is significant at the same RH. PVP can better inhibit IRB recrystallization than PVPVA 46. In contrast, PVPVA 46 can better maintain the amorphous form of OXA than PVP. The thermodynamic phase diagrams of amorphous API/polymer formulations at 60% RH and anhydrous conditions were predicted using perturbed chain statistical associated fluid theory (PC-SAFT) and the Gordon–Taylor equation. Furthermore, the electrostatic potential (ESP) and binding energies between APIs and polymers were calculated with density functional theory (DFT), which explained the molecular interaction mechanism of ASDs. This work is expected to guide the screening of excipients and API loadings for designing ASDs and the selection of storage conditions.