Purpose Hypertrophic resistance exercise (HRE) induces central and peripheral fatigue. However, more detailed information about changes in corticospinal excitability remains to be elucidated. Methods Eleven volunteers participated in the upper arm HRE which included one repetition maximum (1 RM) control contractions and three sets of 13 RM (SET1–3). Transcranial magnetic stimulation (TMS) was applied during maximal isometric voluntary contraction (MVC) at the end of each set and during control contractions to study changes in corticospinal excitability. Electrical stimulation was used in order to measure peripheral changes. Results MVC decreased after each set when compared to control contractions. Motor evoked potential (MEP) were 138.7 ± 52.7 % (p < 0.05), 130.4 ± 44.7 and 113.1 ± 31.4 % after SET1, SET2 and SET3, respectively, when compared to pre-exercise value. A significant reduction in MEP area between SET1 and SET3 (p < 0.05) was observed while silent period (SP) duration increased (~151–165 ms, p < 0.05) simultaneously between these sets. TMS-evoked twitch force during MVC increased significantly following each set when compared to pre-exercise value. Simultaneously, a significant reduction was observed in resting twitch force over the sets. Conclusions The results of this study clearly support the existence of both central and peripheral fatigue during HRE of elbow flexors. However, changes in the MEP area and SP suggest that during HRE of the elbow flexors, the corticospinal excitability increases first, until at some point, supraspinal fatigue takes over.