Our previous research has demonstrated that the spinal cord undergoes epigenetic and molecular alterations following non-severe burn injury (BI). However, the primary somatosensory cortex (S1), crucial for pain perception, remains unexplored in this context. Here, we investigated transcriptomic alterations in the S1 cortex of mice subjected to BI or formalin application (FA) to the hind paw, utilizing RNA sequencing (RNA-seq) one hour after injury. RNA-seq identified 1116 differentially expressed genes (DEGs) in BI and 136 DEGs in formalin-induced inflammatory pain. Notably, 82.4% of DEGs in BI and 32.4% in FA were downregulated. A total of 42 upregulated and 17 downregulated overlapping DEGs were identified, indicating significant differences in the cortical processing of pain based on its origins. Gene Ontology analysis reveals that BI upregulated mitochondrial functions and ribosome synthesis, whereas axon guidance, synaptic plasticity, and neurotransmission-related processes were downregulated. By contrast, formalin treatment mainly impacted metabolic processes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis highlights the significance of retrograde endocannabinoid signaling (REC) in the response to burn injury. These findings demonstrate that transcriptomic remodeling in the S1 cortex is dependent on the sensory modality and suggest that the REC network is activated during acute pain responses following BI.