Agricultural weeds may originate from wild populations, but the genetic mechanisms underlying this transition to weediness remain largely unknown. Analysis of weedy-wild paired populations from multiple independent locations may provide parallel evidence to identify key genetic variations during this evolutionary shift. With transcriptome data from 67 giant ragweed samples collected from different locations, we established a comprehensive pipeline to perform analysis on both genetic variants and expression alterations. We found geographically separated populations may originate independently from nearby wild populations, but the subsequent spreading of weedy populations also occurred locally. By using eight closely related weedy-wild paired populations, we identified hundreds of specifically expressed transcripts with commonly shared functions in biotic and abiotic responses pathways in weedy populations. In addition, we found that genes involved within particular biological pathways may have altered gene expression diversity or gene coexpression networks in weedy populations compared with wild populations. Our study suggests an integrated route with independent originations combined with the subsequent spreading of certain weedy populations for the origin of weedy giant ragweed and provides several lines of evidence to support the idea that gene expression reprogramming may play a key role in convergent evolution of weedy species.