Background: Low-sodium (LS) salt substitution is recognized for its potential to reduce blood pressure (BP), but most research relies on office BP measurement (OBPM). There is a lack of data on salt substitution’s effect on target organs, such as the kidney as measured by the urine albumin-to-creatinine ratio (UACR), and its impact on inflammatory cytokines, particularly high-sensitivity C-reactive protein (hs-CRP). To evaluate the effect of LS salt substitution on ambulatory BP measurement (ABPM), kidney function, and inflammation in middle-aged and elderly hypertensive patients. Methods: In this 12-month prospective, multi-center, randomized, double-blind study, 352 hypertensive patients were randomly assigned to the normal salt (NS) group (n = 176) or the LS group (n = 176) at a 1:1 ratio. ABPM, fasting blood, and morning first spot urine samples were obtained at baseline and the endpoint. Results: Of the 352 patients, 322 completed all follow-up surveys, and 301 underwent ABPM. In the LS roup, significant reductions were observed in 24-hr systolic BP (–2.3 mmHg), 24-hr diastolic BP (–1.5 mmHg), daytime systolic BP (–2.6 mmHg), daytime diastolic BP (–1 mmHg), and nighttime systolic BP (–0.1 mmHg) compared to the NS group (all p 0.05). However, the change in nighttime diastolic BP was not statistically significant (–0.3 vs. 1.1 mmHg, p = 0.063). Additionally, the LS group showed a more substantial decrease in UACR (–2.05 vs. –7.40 µg/mg, p = 0.004) and hs-CRP (–0.06 vs. –0.24 mg/L, p = 0.048) compared to NS. Conclusions: LS salt substitution significantly decreased ABPM, suggesting a notable impact on hypertension. Furthermore, it demonstrated a protective impact on kidney function, as evidenced by changes in UACR. Additionally, LS salt substitution appeared to reduce inflammation, indicated by the decrease in hs-CRP levels. Clinical Trial Registration: The study was registered in the Chinese clinical trial registry (registration number: ChiCTR1800019727).