Background: Preeclampsia, a pregnancy complication marked by hypertension after 20 weeks of gestation, arises from placental factors that impair maternal vascular function. C-type natriuretic peptide (CNP), known for its vasodilatory role, may help counter preeclampsia-related vascular dysfunction. This study aimed to explore the effect of CNP on preeclampsia risk using the Mendelian randomization (MR) framework. Methods: Genetic instrumental variables that mimic the effects of CNP signaling (through natriuretic peptide receptor 2 [NPR2] activation or reduced NPR3-mediated clearance) were identified in the genes encoding the two receptors. This discovery emerged from a multiancestry genome-wide association study (GWAS) involving over 5 million individuals. Female-specific genetic association estimates were obtained from individual-level data comprising 198,402 female participants in the UK Biobank. Two-sample MR analyses were conducted to investigate the effects of NPR2 activation and NPR3 function on preeclampsia, utilizing the largest publicly available GWAS on preeclampsia, which included 296,824 female participants. Results: Genetically proxied reduced NPR3 function was associated with a lower risk of preeclampsia (odds ratio (OR): 0.46, 95% confidence interval 0.30-0.69). In contrast, genetically proxied increased NPR2 activation lacked significant association, likely due to underpowered genetic instruments. Sensitivity analyses indicated robust findings with minimal pleiotropy, meaning the genetic variants used primarily influenced preeclampsia through the intended biological pathway rather than affecting multiple unrelated traits. Conclusion: This study employed the MR paradigm to provide genetic evidence supporting the protective effects of CNP (through reduced NPR3 function) on the risk of preeclampsia. However, it is important to gather additional evidence from other sources before moving forward with clinical development efforts to explore CNP as a potential treatment for preeclampsia.