ABSTRACT: Phytophthora root and stem rot (PRR) caused by oomycete pathogens in the Phytophthora genus poses a significant threat to soybean productivity. While resistance mechanisms against Phytophthora sojae have been extensively studied, the molecular basis underlying immune responses to the newly recognized pathogen, Phytophthora sansomeana, remains largely unknown. In this study, we investigated transcriptomic and epigenetic responses of two resistant (Colfax and NE2701) and two susceptible (Williams 82 and Senaki) soybean lines at four time points (2, 4, 8, and 16 hours post inoculation, hpi) after P. sansomeana inoculation. Through comparative transcriptomic analyses, we identified a greater number of differentially expressed genes (DEGs) upon pathogen inoculation in the resistant lines compared to the susceptible lines, predominantly at 8 and 16 hpi. These DEGs were associated with multiple phytohormones, including ethylene, salicylic acid, and jasmonic acid, along with various transcription factors and signaling cascade proteins. Moreover, DE transposable elements (TEs) were predominantly up-regulated after inoculation, and we found that TEs differentially transcribed in a resistant line were enriched near genes. Notably, we identified a long non-coding RNA (lncRNA) that was significantly differentially transcribed after inoculation exclusively in the resistant lines, potentially regulating two flanking LURP-one-related genes, known as key defense mediators in Arabidopsis against oomycete pathogens. Furthermore, DNA methylation analysis revealed increased CHH (H = A, T, or C) methylation levels in lncRNAs after inoculation, with delayed responses in the resistant line compared to the susceptible line. Overall, our results provide insights into the molecular mechanisms underlying resistance to P. sansomeana in soybean and underscore the potential role of lncRNAs and epigenetic regulation in plant defense responses.