ObjectivesThe objective of this study was to investigate how kinesiophobia and self-efficacy explain the relationship between fatigue and physical activity (PA) in post-coronary artery bypass grafting (post-CABG) patients over the age of 45.DesignA prospective multicentre and cross-sectional study.SettingThe study was conducted in four public tertiary hospitals in China.ParticipantsA total of 1278 patients who underwent CABG surgery were selected from the case pool, with their surgeries occurring between 3 and 19 months prior to selection. Out of 1038 patients who met the inclusion criteria and were invited to participate in the study, 759 patients agreed to participate and complete the questionnaire. Ultimately, 376 questionnaires were deemed eligible and included in the analysis.Primary and secondary outcome measuresThe questionnaire included the following scales: the Chinese version of the Multidimensional Fatigue Inventory (MFI-20), the Tampa Scale for Kinesiophobia Heart (TSK-SV Heart), the Cardiac Exercise Self-Efficacy Instrument (CESEI) and the International Physical Activity Questionnaire-Long (IPAQ-L). A serial mediation model was used to test whether the association between fatigue and PA was mediated by kinesiophobia and self-efficacy, in the overall sample and subsamples defined by age.ResultsThe results confirmed that fatigue was directly (95% CI (−5.73 to −3.02)) associated with PA. Higher kinesiophobia (95% CI (−0.16 to −0.05)) or lower PA self-efficacy (95% CI (−0.11 to −0.02)) were parallel pathways through which higher fatigue impediment reduced PA levels. In both subgroups, the street pathways of kinesiophobia and self-efficacy were altered. In the age, 45–60 years group, kinesiophobia (Boot 95% CI (−0.19 to−0.05)) was a mediator of fatigue on PA levels, while in the 61–75 years age group, self-efficacy (Boot 95% CI (−0.17 to −0.04)) was a mediator of fatigue on PA levels.ConclusionsA clear relationship between fatigue and PA was mediated by both kinesiophobia and self-efficacy. Furthermore, our findings highlight the importance of adapting the intervention according to the age of the patients, mainly by reducing patients’ kinesiophobia in patients aged 45–60 years and increasing patients’ self-efficacy in patients aged 61–75 years. It may be possible to improve PA levels in post-CABG patients over 45 years of age by eliminating kinesiophobia and increasing self-efficacy.