Aims This study tested the hypothesis that high doses of anti‐inflammatory drugs would attenuate the adaptive response to resistance training compared with low doses. Methods Healthy men and women (aged 18–35 years) were randomly assigned to daily consumption of ibuprofen (IBU; 1200 mg; n = 15) or acetylsalicylic acid (ASA; 75 mg; n = 16) for 8 weeks. During this period, subjects completed supervised knee‐extensor resistance training where one leg was subjected to training with maximal volitional effort in each repetition using a flywheel ergometer (FW), while the other leg performed conventional (work‐matched across groups) weight‐stack training (WS). Before and after training, muscle volume (MRI) and strength were assessed, and muscle biopsies were analysed for gene and protein expression of muscle growth regulators. Results The increase in m. quadriceps volume was similar between FW and WS, yet was (averaged across legs) greater in ASA (7.5%) compared with IBU (3.7%, group difference 34 cm3; P = 0.029). In the WS leg, muscle strength improved similarly (11–20%) across groups. In the FW leg, increases (10–23%) in muscle strength were evident in both groups yet they were generally greater (interaction effects P < 0.05) for ASA compared with IBU. While our molecular analysis revealed several training effects, the only group interaction (P < 0.0001) arose from a downregulated mRNA expression of IL‐6 in IBU. Conclusion Maximal over‐the‐counter doses of ibuprofen attenuate strength and muscle hypertrophic adaptations to 8 weeks of resistance training in young adults. Thus, young individuals using resistance training to maximize muscle growth or strength should avoid excessive intake of anti‐inflammatory drugs.