Substantial evidence has established the negative impact of inhalation exposure to welding fumes on respiratory functions. The aim of the present study was to investigate the effect of welding fume inhalation on expression of molecules that function as sensors, transducers and effectors of DNA damage response (DDR) in the respiratory tract of male Sprague-Dawley rats. Animals were exposed to 50 mg/m3 stainless steel welding fumes for 1 h/d for 4, 8, and 12 weeks, respectively. Histological examination demonstrated preneoplastic changes in trachea and bronchi with focal atelectasis and accumulation of chromium (Cr) in the lungs. This was associated with elevated levels of DNA damage markers (8-oxodG, γH2AX), ATM phosphorylation, cell cycle arrest, apoptosis induction, activation of homologous recombination (HR), non-homologous end joining (NHEJ), and Nrf2 signaling, as well as altered expression of noncoding RNAs (ncRNAs). However, after 12 weeks of exposure, DDR was compromised as reflected by resumption of the cell cycle, repair inhibition, and failure of apoptosis. Data demonstrate that exposure to welding fumes influences two crucial layers of DDR regulation, phosphorylation of key proteins in NHEJ and HR, as well as the ncRNAs that epigenetically modulate DDR. Evidence indicates that marked DNA damage coupled with non-productive DNA repair and apoptosis avoidance may be involved in neoplastic transformation.