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Introduction: As a leading cause of pregnancy and fetal mortality, pre-eclampsia impacts about 5–8% of pregnancies globally. To date, few studies have focused on the role played by (NOD)-like receptors protein 3 (NLRP3) in peripheral blood in early-onset pre-eclampsia (PE). In this study, we investigated whether NLRP3 expression in monocytes before 20 weeks of gestation was associated with an increased risk of early-onset PE. Methodology: During the study period from 2019 to 2021, women with singleton pregnancies were enrolled in this prospective study at the General Hospital of Northern Theater Command. A generalized additive model (GAM) and logistic regression models were applied to determine any association between NLRP3 and the risk of early-onset PE. Results: In total, 571 and 48 subjects were included in the control and pre-eclampsia groups, respectively. The GAM and logistic regression models showed that NLRP3 was a significant factor for PE occurrence. The area under the curve, accuracy, specificity, sensitivity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 0.86, 0.82, 0.95, 0.72, 15.17, 0.29, and 52.0, respectively. Conclusion: The monitoring for NLRP3 in peripheral blood may be a potential, prospectively identifying risk factor for preeclampsia. [ABSTRACT FROM AUTHOR]