Ganoderma colossus, a pan-tropical mushroom of Ganodermataceae fungi, grows very fast on lignocellulose-rich substrates and shows remarkable thermotolerance. However, the genomic features and molecular mechanisms of G. colossus related to lignocellulose degradation, high temperature growth and triterpene biosynthesis are largely unknown. In this study, we isolated the G. colossus strain capable of growing at 50 °C and obtained a high-quality genome sequence of this strain. Transcriptome profiling under different substrates highlighted the upregulations of CAZymes (GH3, GH10, and GH28), CYP450 genes, and specific factors (TFs) such as HSF and Zn2C6 in the presence of lignocellulose substrates, showing a preference and high capacity for cellulose and hemi-cellulose degradation. At 45 °C, the protein modification genes (HSP90 and DnaJ), stress-response TFs (C2H2, Zn2-C6, and GATA), detoxification and metabolism genes CYP450, and CAZyme genes (GH3, AA3, and GT2) were significantly upregulated; however, HSP20 and oxidative phosphorylation genes were notably suppressed. Co-expression analysis of two transcriptomes identified 74 shared DEGs linking lignocellulose degradation and heat adaptation, including TFs, CAZymes, and CYP450. These data suggested that a novel regulatory model where Zn2-C6 TFs were involved in activating CAZymes and CYP450s to enhance thermotolerance and lignocellulose substrate utilization. In addition, we identified the pathway and key regulatory genes involved in triterpene biosynthesis in G. colossus. This study provided the first genome of G. colossus and dissected its molecular mechanisms of adaptability to high-temperature and lignocellulose-rich environments, with significant implications for heat-resistant breeding and advancing the agricultural waste utilization by white rot fungi.