The study identified in a mouse model of preterm birth a Ccl2+fib fibroblast subpopulation that significantly expanded under pathological conditions. Mendelian randomization analysis showed that KLF4 is a genetic risk factor for preterm birth with OR = 1.32 (95% CI: 1.12–1.56), without reverse causality. KLF4 was increased in the blood and placental tissues of patients with preterm delivery. In LPS-induced placental inflammation, KLF4 increased in a dose-dependent manner, while its knockdown suppressed TNF-α and IL-1β secretion and reduced apoptosis. In a rat model of infection, knockdown of KLF4 reduced the incidence of preterm birth from 65% to 20% and significantly reduced the number of stillborn fetuses. Thus, KLF4 controls the inflammatory network through Ccl2+ fibroblasts and represents a potential therapeutic target.