Background: Hypertension is closely associated with excessive sodium intake, and low-sodium salt has been shown to lower blood pressure. However, whether low-sodium salt interacts with genetic variation related to salt sensitivity of blood pressure is unclear. Methods: A total of 259 hypertensive patients who completed the previous 3 years of a low-sodium salt vs. normal salt intervention were included in our study. Genetic risk scores (GRSs) of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were respectively built for each participant. A general linear regression model and a generalized mixed model were applied to identify the interaction effects between low-sodium salt intervention and ENaC genetic variation on SBP/DBP changes and trajectories over 3 years. Findings: during the 3-year intervention, both SBP and DBP levels showed a significant decline in the low-sodium salt intervention group than those in the normal salt intervention group over 3 years (Psalt intervention group = 0.001 for SBP and Psalt intervention group = 0.006 for DBP). Furthermore, a gene-diet interaction was found for the SBP change trajectory over 3 years (PSBP-GRS×salt intervention group = 0.011); specifically, significant SBP reductions were found between salt intervention groups in the high SBP-GRS group (-18.77 vs. -9.58 mmHg, Psalt intervention group = 0.001), but not in the low SBP-GRS group (-15.71 vs. -14.62 mmHg, Psalt intervention group = 0.791). No interaction effect between low-sodium salt intervention and genetic variation of ENaC was found for changes in DBP. Conclusions: Higher ENaC genetic variation is associated with a greater reduction in SBP in response to a low-sodium salt intervention. Hypertensive patients with higher ENaC genetic variation may experience a greater benefit in SBP reductions by consuming low-sodium salt. (Trial registration: chiCTR-TRC-09000538, https://www.chictr.org.cn).