Circular leaf spot (CLS) disease, primarily caused by the fungal pathogen Colletotrichum siamense, infects rubber trees and has emerged as a significant threat to the primary source of natural rubber. Understanding the candidate genes of clonal resistance to this disease is crucial for ensuring stable rubber production. Here, comparative transcriptomic analysis via RNA-sequencing provides an informative dataset of differentially expressed genes for the defense responses of two rubber tree clones, susceptible RRIM600 and resistant RRIT3904, after infection with C. siamense for one week. The results revealed a growth-defense trade-off in the RRIT3904 clone involving the downregulation of photosynthesis-related genes and activation of amino acid metabolism, suggesting metabolic remodeling for immune signaling and defense-related precursor synthesis in host resistance. Conversely, the susceptible clone RRIM600 exhibited upregulation of photosynthesis genes and a decline in secondary metabolite biosynthesis, which potentially reflects metabolic hijacking of C. siamense in this clone. Key upregulated genes in RRIT3904 include SPX-domain-containing proteins, suggesting balanced phosphate homeostasis in host resistance. Differentially expressed genes between clones that were mock-inoculated versus C. siamense-infected were also analyzed. Together, these results highlight critical pathways that distinguish resilience from susceptibility, offering a molecular basis for breeding programs aimed at mitigating CLS disease in rubber tree plantations.