Background It has been hypothesized that post-stroke fatigue (PSF) is associated with reduced physical activity (PA) and impaired physical fitness (fitness). Understanding associations between PSF and PA and/or fitness could help guide the development of targeted exercise interventions to treat PSF. Aims Our systematic review and meta-analysis aimed to investigate PSF’s associations with PA and fitness. Summary of review Following a registered protocol, we included studies with cross-sectional or prospective observational designs, published in English or a Scandinavian language, that reported an association of PSF with PA and/or fitness in adult stroke survivors. We searched Medline, Embase, AMED, Cinahl, PsycInfo, ClinicalTrials.gov, and World Health Organization’s International Clinical Trials Registry Platform from inception to Nov 30, 2022. Risk of bias was assessed using Quality in Prognosis Studies. Thirty-two unique studies (total n=4721 participants, 55% male), and three study protocols were included. We used random-effects meta-analysis to pool data for PA and fitness outcomes, and vote-counting of direction of association to synthesize data that could not be meta-analyzed. We found moderate-certainty evidence of a weak association between higher PSF and impaired fitness (meta r=−0.24; 95% CI=−0.33, −0.15; n=905, 7 studies), and very low-certainty evidence of no association between PSF and PA (meta r=−0.09; 95% CI=−0.34, 0.161; n=430, 3 studies). Vote-counting showed a higher proportion of studies with associations between higher PSF and impaired fitness (p̂=0.83; 95% CI=0.43, 0.97; p=0.22, n=298, 6 studies), and with associations between higher PSF and lower PA (p̂=0.75; 95% CI=0.47, 0.91; p=0.08, n=2566, 16 studies). Very low- to moderate-certainty evidence reflects small study sample sizes, high risk of bias, and inconsistent results. Conclusions The meta-analysis showed moderate-certainty evidence of an association between higher PSF and impaired fitness. These results indicate that fitness might protect against PSF. Larger prospective studies, and randomized controlled trials evaluating the effect of exercise on PSF is needed to confirm these findings. This study had no funding. PROSPERO 2021 CRD42021216435