Chronic histiocytic intervillositis of unknown origin (CHI) is a rare placental disorder associated with adverse pregnancy outcomes, frequent recurrence, and a lack of effective preventive strategies. Recent insights indicate a potential link between CHI-associated inflammatory lesions and the inflammasome pathway, suggesting innovative therapeutic avenues. This study aims to elucidate the role of the inflammasome pathway in CHI through comprehensive transcriptomic analysis of grade 2 or 3 histopathologic CHI samples, paired with placental controls. Additionally, we present case studies of three individuals with recurrent CHI who received treatment with anakinra and colchicine throughout pregnancy, resulting in improved perinatal outcomes. Notably, all cases led to the birth of healthy, full-term infants, with reduced or absent intervillositis recurrence. Placental assessment unveiled heightened activation of the NLRP3-PYCARD inflammasome pathway and IL-1β processing in CHI samples, with downregulation observed in treated pregnancy samples devoid of intervillositis. Collectively, these findings suggest a potential therapeutic role for targeting the inflammasome pathway in preventing recurrent CHI in pregnant individuals. The molecular insights provided herein open doors for innovative interventions in managing this rare placental disorder, warranting further investigation and consideration.