Rust (Melampsora apocyni) on Apocynum venetum is the major constraint to the commercial development of this medicinal herb. To determine the factors influencing rust intensity (maximum disease index [DI max ]), rust was investigated from 2011 to 2015 in both cultivated and wild A. venetum plants. Partial least squares path modeling (PLS-PM) was used to analyze the paths and extent of the factors related to pathogen, environment, and host that affect rust intensity. DI max exhibited considerable variations across years and study sites, with variations linked to various factors fostering disease development. PLS-PM explained 80.0 and 70.1% of variations in DI max in cultivated and wild plants, respectively. Precipitation was the key factor determining DI max in both cultivated and wild plants (path coefficient [PC] = 0.313 and 0.544, respectively). In addition, the topsoil water content in cultivated plants and the total vegetation coverage in wild plants were also critical determinants of DI max via their effects on the microclimatic factor (contribution coefficients [CC] = 0.681 and 0.989, respectively; PC = 0.831 and 0.231, respectively). In both cultivated and wild plants, host factors were mainly dominated by A. venetum density (CC = 0.989 and 0.894, respectively), and their effect on DI max via the microclimatic factor (PC = 0.841 and 0.862, respectively) exceeded that via the inoculum factor (PC = 0.705 and 0.130, respectively). However, the indirect effects led to DI max variation, while the dilution effect on host (CC = 0.154) from weed in wild plants led to the indirect effect size in wild plants of 0.200, which was lower than _0.699 in cultivated plants.