PURPOSE: Osteoarthritis (OA) pain can arise from inflammatory cytokines sensitizing neurons that innervate the temporomandibular joint (TMJ) and knee. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based epigenome editing enables targeted repression of inflammatory receptors and offers a promising strategy to modify disease mechanisms. This study tested whether CRISPR epigenome editing of interleukin-1 receptor type 1 (IL1R1) in trigeminal ganglia (TG; TMJ-innervating) and dorsal root ganglia (DRG; knee-innervating) neurons could reduce OA-associated sensitization. METHODS: OA cartilage was collected from knee replacement patients and compared with healthy cadaveric cartilage. Rat TG and DRG neurons were cultured with IL-1β on tissue culture plastic or cartilage explants, loaded with calcium dye, and subjected to thermal stimulation. Neurons were transduced with lentiviral CRISPR-dCas9-KRAB vectors targeting IL1R1 or with nontargeting controls, and heat-evoked calcium transients were measured. RESULTS: Exposure to IL-1β and OA cartilage both increased the proportion of TG and DRG neurons exhibiting heat-induced calcium transients compared with controls. CRISPR epigenome editing of IL1R1 abolished sensitization in DRG neurons, restoring responses to healthy cartilage levels. In TG neurons, editing reduced maximum calcium responses to baseline but did not fully normalize the percentage of sensitized cells, suggesting additional OA factors contribute to TMJ pain. CONCLUSION: CRISPR epigenome editing of IL1R1 in joint-innervating neurons reduces OA cartilage-induced sensitization. These results highlight differential mechanisms underlying OA cartilage driven DRG and TG neuron sensitization and establish epigenome editing as a potential therapeutic strategy to target OA-associated sensitization in the knee and TMJ.