The wrist extensors demonstrate an earlier fatigue onset than the wrist flexors. However, it is currently unclear whether fatigue induces unique changes in muscle activity or corticospinal excitability between these muscle groups. The purpose of this study was to examine how sustained isometric wrist extension/flexion maximal voluntary contractions (MVCs) influence muscle activity and corticospinal excitability of the forearm. Corticospinal excitability to three wrist flexors and three wrist extensors were measured using motor evoked potentials (MEPs) elicited via transcranial magnetic stimulation. Responses were elicited while participants exerted 10% of their maximal handgrip force, before and after a sustained wrist flexion or extension MVC (performed on separate sessions). Post-fatigue measures were collected up to 10-min post-fatigue. Immediately post-fatigue, extensor muscle activity was significantly greater following the wrist flexion fatigue session, although corticospinal excitability (normalized to muscle activity) was greater on the wrist extension day. Responses were largely unchanged in the wrist flexors. However, for the flexor carpi ulnaris, normalized MEP amplitudes were significantly larger following wrist extension fatigue. These findings demonstrate that sustained isometric flexion/extension MVCs result in a complex reorganization of forearm muscle recruitment strategies during hand-gripping. Based on these findings, previously observed corticospinal behaviour following fatigue may not apply when the fatiguing task and measurement task are different.