Lonicera macranthoides Hand.−Mazz. is a valuable medicinal plant in China and is used worldwide. This study aimed to predict its suitable habitats in China using the MaxEnt model, and to assess the effects of environmental variables on indicator ingredients (chlorogenic acid, macranthoidin B, and dipsacoside B) via HPLC and chemometrics. Furthermore, to explore the molecular mechanisms underlying environment−quality relationships, preliminary indoor versus outdoor stress experiments were conducted, analyzing the expression of chlorogenic acid biosynthetic genes using qRT−PCR. The results showed that precipitation of the driest month was the most influential variable affecting distribution. Currently, suitable areas are mainly located between 21° N and 33° N. During the Last Glacial Maximum (LGM), habitats were more expansive, whereas they contracted during the Mid−Holocene (MH). Future projections indicated habitat loss under the SSP585 scenario, which was partially mitigated under the SSP126 scenario by 2090 S. Higher contents of chlorogenic acid and saponins were found in suitable habitats and were associated with soil, altitude, and precipitation. Notably, outdoor combined stress (low temperature and low sunshine) significantly regulated the expression of LmPAL, LmCHS, LmCHI, LmC4H, LmCCoAOMT, and LmANS. This study serves as a scientific basis for the conservation, sustainable cultivation, and stress−oriented breeding of L. macranthoides in China.