ObjectiveTo explore the predictive value of serum homocysteine (Hcy), 25-hydroxy vitamin D (25-OHD), and uterine artery blood flow parameters for preeclampsia (PE) during early pregnancy. Methods In this prospective cohort study, 2 200 pregnant women who underwent prenatal examinations and delivered at the First People"s Hospital of Lianyungang between November 2021 and May 2023 were included. Serum Hcy and 25-OHD levels were measured during the regular prenatal examination at 11-13_⁺⁶ weeks of gestation, along with ultrasound assessment of uterine artery blood flow parameters, such as peak systolic velocity/end diastolic velocity (S/D), pulsatility index (PI), and resistance index (RI). These participants were categorized into PE group (141 cases) and control group (2 059 cases) according to whether developed PE by the 20th week of gestation. Two independent sample t-test and Chi-square test were used to compare the general clinical data, Hcy, 25-OHD, and uterine artery blood flow parameters between the two groups. Multivariate logistic regression analysis was employed to identify independent risk factors for PE. The receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive value of the markers used along or in combination for PE. A PE risk nomogram was developed using R software, with calibration curves internally validating the nomogram prediction model. Results Serum Hcy levels [(8.39±1.22) vs. (6.07±1.34) μmol/L, t=15.03], S/D (5.22±2.03 vs. 3.19±1.64; t=7.93), PI (2.34±0.94 vs. 1.31±0.69, t=8.65), and RI (1.81±0.44 vs. 0.67±0.30, t=9.26) were higher in the PE group than in the control group, whereas the levels of 25-OHD were lower [(17.76±3.18) vs. (24.76±5.08) μg/L, t=﹣16.97] (all P<0.001). Multivariate logistic regression analysis indicated that Hcy (OR=2.58, 95%CI: 2.03-3.27), S/D (OR=1.56, 95%CI: 1.33-1.84), PI (OR=2.06, 95%CI: 1.45-2.94) and RI (OR=2.97, 95%CI: 1.68-5.24) were independent risk factors for PE, while 25-OHD was an independent protective factor (OR=0.80, 95%CI: 0.72-0.88). ROC curve analysis showed that the optimal cut-off values for predicting PE were 6.65 μmol/L for Hcy, 23.43 μg/L for 25-OHD, 2.93 for S/D, 1.26 for PI, and 0.85 for RI, with the sensitivity of 0.908, 0.699, 0.752, 0.844, and 0.589, respectively, and the specificity of 0.783, 0.915, 0.574, 0.578, and 0.891, respectively. The performance of these markers used in combination for predicting PE was superior, with an area under the curve of 0.967 (95%CI: 0.956-0.979), the sensitivity of 0.969, and the specificity of 0.865. Internal validation showed that the calibration curve of the nomogram approximated the original curve and the ideal curve, with a concordance index of 0.966 (95%CI: 0.656-0.993), suggesting a high model fit. Conclusion The PE risk nomogram constructed based on serum Hcy, 25-OHD, and the uterine artery blood flow parameters S/D, PI, and RI in early pregnancy provides good predictive value for PE and can offer guidance for early clinical screening or prediction of PE.