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Peripheral nervous system (PNS) toxicity assessment in non-clinical safety studies is challenging and relies mostly on histopathological assessment. The present work aims to identify blood-based biomarkers that could detect peripheral neuropathy in rats upon exposure to neurotoxic compounds. Three anticancer agents (oxaliplatin, cisplatin, paclitaxel) and a developmental compound (NVS-1) were assessed in male rats (Wistar Han). Clinical and/or functional endpoints (i.e., electronic Von Frey, Cold Plate, and Paw Pressure tests) and blood biomarkers (i.e., neurofilament light chain (NfL), neurofilament heavy chain (NF-H), microtubule-associated protein Tau (Tau), neuron specific enolase (NSE), vascular endothelial growth factor A (VEGFA), and glial fibrillary acidic protein (GFAP)) were assessed. Drug exposure and histopathological evaluations were conducted on selected nervous tissues. Oxaliplatin, cisplatin and paclitaxel treatment resulted in a significant decrease of nociceptive thresholds. Clinical signs suggestive of PNS toxicity were observed with NVS-1. NfL was consistently increased in the NVS-1 study and correlated with moderate microscopic findings in dorsal root ganglia (DRG). Only minimal microscopic findings were observed in oxaliplatin-treated animals, whereas no treatment-related microscopic findings were observed in animals treated with cisplatin and paclitaxel. For all compounds, exposure was confirmed in the PNS tissues. Clinical and functional changes were observed with all the compounds evaluated. NfL levels in plasma proved to be the most sensitive indicator of PNS toxicities, capturing moderate nervous degeneration in DRG. A combined approach that includes both functional assessments and biomarker measurements offers a more comprehensive evaluation than histopathological analysis alone when monitoring drug-induced neurotoxicity in rat models., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Some authors are employees in the companies involved in the studies and may have access to stock/share options. In particular Kuno Wuersch, Eric Johnson, Wilfried Frieauff, Kelley Penrrat, Dominique Brees, Valerie Dubost and Diethilde Theil in Novartis; Warren E. Glaab, Katerina Vlasakova in Merck & Co., Inc., Rahway, NJ, Unites States; Olivier Perrault and Mohamed Slaoui in Sanofi. The other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)