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Aim We compared the pharmacokinetic (PK) profiles of co‐crystal of tramadol–celecoxib (CTC) vs. each reference product (alone and in open combination) after single (first dose) and multiple dosing. Methods Healthy adults aged 18–50 years received, under fasted conditions, 15 twice‐daily doses of the following treatments (separated by ≥14‐day washout): 200 mg immediate‐release (IR) CTC (equivalent to 88 mg tramadol and 112 mg celecoxib; treatment 1); 100 mg IR tramadol (treatment 2), 100 mg celecoxib (treatment 3); and 100 mg IR tramadol and 100 mg celecoxib (treatment 4). The treatment sequence was assigned by computer‐generated randomization. PK parameters were calculated using non‐compartmental analysis. Parameters for CTC were adjusted according to reference product dose. Results A total of 30 subjects (20 males, mean age 35 years) were included. Multiple‐dose tramadol PK parameters for treatments 1, 2 and 4, respectively, were 551, 632 and 661 ng ml−1 [mean maximum plasma concentration (C max)]; 4796, 4990 and 5284 ng h ml−1 (area under the plasma concentration–time curve over the dosing interval at steady state); and 3.0, 2.0 and 2.0 h (median time to C max at steady state). For treatments 1, 3 and 4, multiple‐dose celecoxib PK parameters were 445, 536 and 396 ng ml−1; 2803, 3366 and 2897 ng h ml−1; and 2.0, 2.0 and 3.0 h. Single‐dose findings were consistent with multiple‐dose data. Types of adverse events were consistent with known reference product safety profiles. Conclusion After single (first dose) and multiple dosing, PK parameters for each active pharmaceutical ingredient in CTC were modified by co‐crystallization compared with reference products alone or in open combination.