Diabetic peripheral neuropathy impacts patient quality of life. Increased Mer tyrosine kinase expression has been demonstrated in such patients, yet its mechanism remains unclear. This study established type 2 diabetes mellitus and diabetic peripheral neuropathy models in Sprague Dawley rats via low-dose streptozotocin and a high-fat diet. Mer tyrosine kinase-specific inhibitors were administered by gavage once daily for 2 weeks. Sciatic nerve conduction velocity and nerve structure were measured. The levels of Mer tyrosine kinase, nuclear factor kappa-light-chain-enhancer of activated B cells, tumor necrosis factor-alpha, interleukin-1 beta, and relevant biochemical indexes were detected. The study revealed Mer tyrosine kinase upregulation in type 2 diabetes mellitus and more so in diabetic peripheral neuropathy groups. Inhibiting Mer tyrosine kinase led to reduced nerve conduction velocity and further deterioration of sciatic nerve structure, as evidenced by structural morphology. Concurrently, serum levels of total cholesterol, glycated hemoglobin, and triglyceride significantly rose. Moreover, nuclear factor kappa-light-chain-enhancer of activated B cells levels increased in both serum and nerve tissue, alongside a significant rise in tumor necrosis factor-alpha and interleukin-1 beta expressions. Mer tyrosine kinase was found to bind to inhibitor of kappa B kinase beta in Schwann cells, establishing inhibitor of kappa B kinase beta as a precursor to nuclear factor kappa-light-chain-enhancer of activated B cells activation. Inhibition of Mer tyrosine kinase exacerbates neuropathy, indicating its protective role in diabetic peripheral neuropathy by suppressing the nuclear factor kappa-light-chain-enhancer of activated B cells pathway, highlighting a potential new target for its diagnosis and treatment.The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).