(1) Background: Ilyonectria robusta can cause ginseng to suffer from rusty root rot. Secondary metabolites (SMs) produced by Bacillus methylotrophicus NJ13 can inhibit the mycelial growth of I. robusta. However, the molecular mechanism of the inhibition and response remains unclear. (2) Methods: Through an in vitro trial, the effect of B. methylotrophicus NJ13’s SMs on the hyphae and conidia of I. robusta was determined. The change in the physiological function of I. robusta was evaluated in response to NJ13’s SMs by measuring the electrical conductivity, malondialdehyde (MDA) content, and glucose content. The molecular interaction mechanism of I. robusta’s response to NJ13’s SMs was analyzed by using transcriptome sequencing. (3) Results: NJ13’s SMs exhibited antifungal activity against I. robusta: namely, the hyphae swelled and branched abnormally, and their inclusions leaked out due to changes in the cell membrane permeability and the peroxidation level; the EC50 value was 1.21% (v/v). In transcripts at 4 dpi and 7 dpi, the number of differentially expressed genes (DEGs) (|log2(fold change)| > 1, p adj ≤ 0.05) was 1960 and 354, respectively. NJ13’s SMs affected the glucose metabolism pathway, and the sugar-transporter-related genes were downregulated, which are utilized by I. robusta for energy production. The cell wall structure of I. robusta was disrupted, and chitin-synthase-related genes were downregulated. (4) Conclusions: A new dataset of functional responses of the ginseng pathogenic fungus I. robusta was obtained. The results will benefit the development of targeted biological fungicides for I. robusta and the study of the molecular mechanisms of interaction between biocontrol bacteria and phytopathogenic fungi.