Background: Oral anticoagulant is a necessary long-term treatment after mechanical valve replacement (MVR), and medication adherence has a great impact on patients with MVR. Although family caregiver burden is negatively correlated with medication adherence, little is known about the underlying mechanism. Purpose: To test whether family caregiver burden influences medication adherence through post-traumatic growth or medication literacy in patients with MVR. Patients and Methods: A total of 206 patients after MVR were included in this cross-sectional study from July 2021 to December 2021. Data regarding medication adherence, family caregiver burden, post-traumatic growth, and medication literacy were collected by questionnaires. Data were analyzed through SPSS, and pathway analysis was conducted by using AMOS, based on the bootstrapping method. Results: Post-traumatic growth was positively associated with medication adherence (r = 0.284, P < 0.05). Post-traumatic growth independently mediated the association of family caregiver burden on medication adherence [β = 0.32, 95% confidence intervals: (−0.016, −0.008)]. The mediated effect value for post-traumatic growth was 0.07, accounting for 24.14% of the total effect. The model's fit indices were adequate. Conclusion:The mediating effect of post-traumatic growth between family caregiver burden and medication adherence existed in patients with MVR. Interventions considering post-traumatic growth may be useful to increase medication adherence and improve patient rehabilitation.