Objective <p>To investigate the associations between serum uric acid (UA) trajectories and the risk of metabolic dysfunction-associated steatotic liver disease (MASLD) in large cohort survey 2019–2021.</p> Methods <p>This cohort health survey included 11,644 participants without MASLD before January 1, 2021. Among them, 5578 (47.90%) were men and 6066 (52.10%) were women. The group-based trajectory model method was applied to identify serum UA trajectories from January 1, 2019, to December 30, 2021. New-onset MASLD events in 2021 were treated as outcomes. A logistic regression model was used to assess associations between UA trajectories and incidence of MASLD.</p> Results <p>Four distinct serum UA trajectories among both sexes were identified: “low-stable” trajectory 1 (<i>n</i> = 783 men; <i>n</i> = 1143 women), “moderate–moderate increasing” trajectory 2 (<i>n</i> = 2794 men; <i>n</i> = 3266 women), “moderate high–moderate increasing” trajectory 3 (<i>n</i> = 1660 men; <i>n</i> = 1464 women), and “high-increasing” trajectory 4 (<i>n</i> = 341 men; <i>n</i> = 193 women). During the 3-year follow-up period, 840 (15.06%) men and 408 (6.72%) women developed MASLD, respectively. Compared with the trajectory 1 group, the trajectory 4 group had the highest risk (odds ration [OR] 2.99 [95% confidence interval {CI} 1.70, 5.24] for men; OR 2.37 [95% CI 1.04, 5.33] for women), followed by the trajectory 3 (OR 2.23 [95% CI 1.52, 3.30] for men; OR 2.37 [95% CI 1.45, 3.92] for women) and trajectory 2 (OR 1.43 [95% CI 1.07, 1.94] for men; OR 1.37 [95% CI 0.93, 2.03] for women) groups.</p> Conclusions <p>High serum UA trajectories were independent risk factors for MASLD in both sexes, which is critical for informing prevention and treatment strategies in public health initiatives and clinical practice.</p>