Changes in the properties of resin-based polymers exposed to the oral environment can emerge when chlorhexidine (CHX) is incorporated to develop bioactive systems for treating denture stomatitis. Three reline resins loaded with CHX were prepared: 2.5 wt% in Kooliner (K), 5 wt% in Ufi Gel Hard (UFI), and Probase Cold (PC). A total of 60 specimens were submitted to physical aging (1000 cycles of thermal fluctuations, 5–55 °C) or chemical aging (28 days of pH fluctuations in artificial saliva, 6 h at pH = 3, 18 h at pH = 7). Knoop microhardness (30 s, 98 mN), 3-point flexural strength (5 mm/min), and surface energy were tested. Color changes (ΔE) were determined using the CIELab system. Data were submitted to non-parametric tests (α = 0.05). After aging, bioactive K and UFI specimens were not different from the controls (resins without CHX) in mechanical and surface properties. Thermally aged CHX-loaded PC specimens showed decreased microhardness and flexural strength but not under adequate levels for function. The color change was observed in all CHX-loaded specimens that underwent chemical aging. The long-term use of CHX bioactive systems based on reline resins generally does not impair removable dentures’ proper mechanical and aesthetic functions.