Despite of the Southeast Asia’s rich medicinal flora, Bangladesh behinds in utilizing these resources for lead anthelmintic compound discovery. Moreover, target-specific resistance and non-target-specific resistance surge have influenced the lead compounds bio-discovery over the past decades. To date, prior researches are limited to basic efficacy tests and conventional extraction protocol. Therefore, the study was designed to assess the anthelmintic potency of 19 tannin-free natural products induced alterations of neurotransmission in C. elegans. The anthelmintic activity was assessed by examining the motility (head thrashes and body bends), mortality, egg hatch inhibition (EHI) and expression of cat-1, ser-1, dat-1, and tba-1 genes. Eleven (11) plant extracts, Azadirachta indica A. Juss., Cassia alata L., Portulaca oleracea L., Saraca asoca (Roxb.) W.J.de Wilde, Eleusine indica L. Gaertn., Persicaria hydropiper L. Delarbre, Foeniculum vulgare Mill., Clerodendrum infortunatum L., Linum usitatissimum L., Hibiscus rosa-sinensis L., and Vitex negundo L. revealed a significant neurobehavioral and developmental impairments in C. elegans. Persicaria hydropiper L. Delarbre @ 1 mg/mL, caused the lowest body bending (31 ± 1.7, p < 0.01), while Eleusine indica L. Gaertn. reduced head thrashing (66.3 ± 3.0, p < 0.01). L. usitatissimum L. exhibited the highest lethality (87.3 ± 1.8%, p < 0.01) and the LD₅₀ values of Eleusine indica L. Gaertn. (0.40 mg/mL) and Linum usitatissimum L. (0.411 mg/mL) were the lowest. Interestingly, C. infortunatum L. exhibited the strongest EHI (97.5 ± 3.0%, p < 0.01). Gene expression analysis revealed a significant down-regulation of the dopaminergic and serotonergic pathway indicating the metabolic and reproductive disruptions. This pioneering research underscores the anthelmintic potency of native plants to advance anthelmintic drug discovery from natural products. This study harnessing the untapped potential of native plants offers a sustainable and nature-based solution to combat parasitic resistance in both humans and animals rooted in traditional ethnobotanical wisdom.