<p>Cobalt-chromium (Co-Cr) alloys have broad applications in dental practice because of their mechanical strength and durability. However, the corrosive oral environment promotes ion release, raising concerns about toxicity. This study assessed the cytotoxic, oxidative stress, and inflammatory effects of ions released from Co-Cr alloys. Co-Cr alloy specimens were subjected to a six-month immersion test in artificial saliva, followed by quantification of released ions via Inductively Coupled Plasma Mass Spectrometry. Cytotoxicity was assessed in human fibroblast cells, and systemic toxicity was evaluated in male mice (<i>n</i> = 20), divided into control and Co-Cr alloy released ions treated groups. Results revealed a progressive release of Co and Cr ions, peaking at three months. The cytotoxicity assay showed reduced fibroblast viability accompanied by a 2-fold upregulation of the pro-apoptotic marker (Bax) and tumor necrosis factor-alpha, along with a 5-fold increase in interleukin-6 expression. Furthermore, Co-Cr alloy released ions induced a significant increase in oxidative damage, as evidenced by elevated thiobarbituric acid reactive substances and DNA frequency breakage. Antioxidants defenses, including glutathione reductase, catalase, and reduced glutathione, were significantly suppressed in hepatic and renal tissues as compared to the control group. Serum biochemical markers revealed impaired hepatic and renal function, accompanied by dyslipidemia. Histopathological analysis confirmed inflammatory infiltration, hepatocellular degeneration, and tubular alterations. Overall, Co-Cr alloy released ions elicit cytotoxic, oxidative, and inflammatory responses at both cellular and systemic levels. These findings highlight the potential health risks of long-term Co-Cr restorations and emphasize the need for the development of safer alternative biomaterials.</p>