This study was conducted to investigate possible histopathological effects and biochemical reflections of intra-articular dexketoprofen trometamol. A total of 24 New Zealand rabbits were included in the study. Blood sampling was carried out from all animals on the first day, then they were randomly allocated either to the control group (Group C, n = 9) or the dexketoprofen trometamol group (Group D, n = 15). Group C underwent each two intra-articular injections of saline, 0.25 mL into right and 0.50 mL into left knee. Group D was injected 0.25 mL (6.25 mg) dexketoprofen trometamol into the right knee and 0.50 mL (12.5 mg) into the left. The groups were divided randomly into three. Tissue and blood samples were collected from Groups C1 and D1 on the first day, C2 and D2 on the second day and C3 and D3 on the 10th day of the study. Interleukin-1 (IL-1β), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) levels were studied. The histopathological examination of C and D groups did not present any deterioration. IL-6 basal levels were significantly higher in Group D2 compared with C2 and C3 compared with D3. Basal TNF-α levels were higher compared with day 1 in Group C1, and IL-6 and CRP levels were higher in Group D3. Also, none of the increases in these values are supported by histopathological evaluation results. Consequently, we suppose that dexketoprofen trometamol does not cause histopathological deterioration in articular cartilage of rabbits, and the increases in biochemical parameters exclusively are not clinically significant.