Purpose No evidence exists regarding the time course and clinical relevance of muscle strength improvements following resistance training in people with multiple sclerosis (PwMS). The purpose of this study was to investigate the temporal course and the clinical meaningfulness of the changes in strength induced by high-intensity resistance training and whether these changes impact on muscle endurance to fatigue and functional outcomes. Methods PwMS with predominantly unilateral hyposthenia of the ankle dorsiflexors underwent a 6-week isokinetic training of the more affected ankle dorsiflexion muscles. Maximal strength was measured at baseline, during the training on a weekly basis, at the end of the intervention (POST) and at the 12-week follow-up. Muscle endurance to fatigue, mobility and walking outcomes were assessed at baseline, POST and follow-up. Reproducibility and responsiveness analyses were performed. Results Significant gains in muscle strength were already detected after 3 weeks of training with no further improvements in the following weeks. These improvements exceeded the cutoff values for relevant changes and were also positively correlated to improved muscle endurance to fatigue and mobility measures. None of the observed changes in muscle performance and functional outcomes was retained at the follow-up. Conclusions Preliminary evidence showed that 3 weeks of high-intensity resistance training induces consistent and meaningful improvements in muscle performance of the ankle dorsiflexors in PwMS. These findings may have practical dose-response and cost-effectiveness implications in the management of MS-induced muscle weakness, potentially enhancing the understanding of the response to training exhibited by PwMS.