Horseweed [Erigeron canadensis L.; syn.: Conyza canadensis (L.) Cronquist (2n = 18), family: Asteraceae] is known as one of the 10 most troublesome and most commonly occurring weeds in 12 categories of broadleaf crops, fruits, and vegetables and is present in 2,540 counties across the United States. Wide phenotypic plasticity coupled with highly adaptive traits and reported allelopathy might have resulted in its rapid spread and extensive presence across the United States, presumably by altering the composition of local plant community. This study for the first time revealed the allelopathic effect of E. canadensis leaf aqueous extract (10%) on seed germination and seedling growth of seven common weeds, namely, Palmer amaranth (Amaranthus palmeri S. Watson), smooth pigweed (Amaranthus hybridus L.), prickly sida (Sida spinosa L.), and pitted morningglory (Ipomoea lacunosa L.), which are native to North America, and non-native lambsquarters (Chenopodium album L.), curly dock (Rumex crispus L.), and barnyardgrass [Echinochloa crus-galli (L.) P. Beauv.]. Erigeron canadensis aqueous extract significantly (P < 0.05) reduced the seed germination and seedling growth of A. hybridus, A. palmeri, R. crispus, and S. spinosa, but showed nonsignificant impacts on I. lacunosa, C. album, and E. crus-galli. Based on synthetical allelopathic effects (SE < 0), the order of inhibition from highest to lowest was as follows: A. hybridus (−0.580), R. crispus (−0.464), A. palmeri (−0.409), S. spinosa (−0.248), C. album (−0.143), I. lacunosa (−0.035), and E. crus-galli (0.009). Liquid chromatography of the E. canadensis aqueous extract identified a total of 38 compounds with previously known allelopathy, including piperidine, choline, 4-hydroxybenzaldehyde, acetonecyanohydrin, gallic acid, 2-furoic acid, genistein, and gentisic acid. The current study, utilizing a petri dish bioassay, explains E. canadensis’s invasive potential and mechanisms for affecting the succession of commonly occurring native and non-native weed species in the southern United States. These results establish a solid foundation for understanding the mechanisms driving the successful invasion of E. canadensis in its native range and provide a valuable theoretical framework for early-warning systems assessing ecological risks.