Objective To estimate 22‐year trends in the prevalence and incidence of scleritis, and the associations of scleritis with infectious and immune‐mediated inflammatory diseases (I‐IMIDs) in the UK. Methods The retrospective cross‐sectional and population cohort study (1997–2018) included 10,939,823 patients (2,946 incident scleritis cases) in The Health Improvement Network, a nationally representative primary care records database. The case–control and matched cohort study (1995–2019) included 3,005 incident scleritis cases and 12,020 control patients matched by age, sex, region, and Townsend deprivation index. Data were analyzed using multivariable Poisson regression, multivariable logistic regression, and Cox proportional hazards multivariable models adjusted for age, sex, Townsend deprivation index, race/ethnicity, smoking status, nation within the UK, and body mass index. Incidence rate ratios (IRRs) and 95% confidence intervals (95% CIs) were calculated. Results Scleritis incidence rates per 100,000 person‐years declined from 4.23 (95% CI 2.16–6.31) to 2.79 (95% CI 2.19–3.39) between 1997 and 2018. The prevalence of scleritis per 100,000 person‐years was 93.62 (95% CI 90.17–97.07) in 2018 (61,650 UK patients). Among 2,946 patients with incident scleritis, 1,831 (62.2%) were female, the mean ± SD age was 44.9 ± 17.6 years (range 1–93), and 1,257 (88.8%) were White. Higher risk of incident scleritis was associated with female sex (adjusted IRR 1.53 95% CI 1.43–1.66, P < 0.001), Black race/ethnicity (adjusted IRR 1.52 95% CI 1.14–2.01, P = 0.004 compared to White race/ethnicity), or South Asian race/ethnicity (adjusted IRR 1.50 95% CI 1.19–1.90, P < 0.001 compared to White race/ethnicity), and older age (peak adjusted IRR 4.95 95% CI 3.99–6.14, P < 0.001 for patients ages 51–60 years versus those ages ≤10 years). Compared to controls, scleritis patients had a 2‐fold increased risk of a prior I‐IMID diagnosis (17 I‐IMIDs, P < 0.001) and significantly increased risk of subsequent diagnosis (13 I‐IMIDs). The I‐IMIDs most strongly associated with scleritis included granulomatosis with polyangiitis, Behçet’s disease, and Sjögren’s syndrome. Conclusion From 1997 through 2018, the UK incidence of scleritis declined from 4.23 to 2.79/100,000 person‐years. Incident scleritis was associated with 19 I‐IMIDs, providing data for rational investigation and cross‐specialty engagement.