Aims: This study aimed to determine the prognostic value of serum uric acid (SUA) on outcomes in heart failure (HF) with preserved ejection fraction (HFpEF), and whether sacubitril–valsartan reduces SUA and use of SUA-related therapies. Methods and results: We analysed 4795 participants from the Prospective Comparison of ARNI [angiotensin receptor–neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF) trial. We related baseline hyperuricaemia (using age and gender adjusted assay definitions) to the primary outcome [cardiovascular (CV) death and total HF hospitalizations]. We assessed the associations between changes in SUA and Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) and other cardiac biomarkers from baseline to 4 months. We simultaneously adjusted for baseline and time-updated SUA to determine whether lowering SUA was associated with clinical benefit. The mean (± standard deviation) age of patients was 73 ± 8 years and 52% were women. After multivariable adjustment, hyperuricaemia was associated with increased risk for the primary outcome [rate ratio 1.61, 95% confidence interval (CI) 1.37–1.90]. The treatment effect of sacubitril–valsartan for the primary endpoint was not significantly modified by hyperuricaemia (P-value for interaction = 0.14). Sacubitril–valsartan reduced SUA by 0.38 mg/dL (95% CI 0.31−0.45) compared with valsartan at 4 months, with greater effect in those with elevated SUA vs. normal SUA (−0.51 mg/dL vs. −0.32 mg/dL) (P-value for interaction = 0.031). Sacubitril–valsartan reduced the odds of initiating SUA-related treatments by 32% during follow-up (P < 0.001). After multivariable adjustment, change in SUA was inversely associated with change in KCCQ-OSS and directly associated with high-sensitivity troponin T (P < 0.05). Time-updated SUA was a stronger predictor of adverse outcomes than baseline SUA. Conclusions: Serum uric acid independently predicted adverse outcomes in HFpEF. Sacubitril–valsartan reduced SUA and the initiation of related therapy compared with valsartan. Reductions in SUA were associated with improved outcomes.