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Background: >94% of new annual leprosy cases are diagnosed in populations co-endemic for soil-transmitted helminths (STH). STH can profoundly dysregulate host immune responses towards Th2 bias, which can be restored over time after deworming. We hypothesize that STH co-infection is associated with leprosy reaction (denoted as simply “reaction” herein) occurrence within a co-endemic population. Methods: A cohort study was performed on a cohort of Nepalese leprosy patients across treatment and diagnostic classifications who were screened by routine fecal smear microscopy and multiplex quantitative PCR (qPCR) for Ascaris lumbricoides (Al), Strongyloides stercoralis (Ss), Ancyclostoma duodenale (Ad) and Necator americanus (Na). Results: Among 145 patients, 55% were positive for ≥1 STH (STH+): 34% Al+, 18% Ss+, 17% Ad + and 5% Na+. Significant inverse STH and reaction relationships were evidenced by the bulk of cases: 63% reaction-negative were STH+ of total cases (p = 0.030) while 65% reaction-positive were STH− in new cases (96; p = 0.023). Strikingly, the majority of STH+ were reaction-negative, even when considering each species: 59% Al+, 60% Ss+, 62% Ad + and 67% Na + of new leprosy cases. Conclusions: Absence of STH co-infection is associated with leprosy reaction at diagnosis within a co-endemic population. This is likely due to immune reconstitution effects after deworming or interruption of chronic STH-mediated immune dysregulation.