Commonalities in adaptive responses to abiotic stressors could contribute to the development of cross-resistance in weeds. The degree to which herbicide-induced changes in weeds parallel those induced by other abiotic stress remains unknown. We investigated the specificity of metabolic perturbations induced by glyphosate and drought across three glyphosate-resistant (GR) and two glyphosate-susceptible (GS) biotypes of Palmer amaranth (Amaranthus palmeri) using global metabolomics approaches. Compared to GS-biotypes, in the absence of stress, the GR-biotypes had a higher abundance of primary metabolites, including sugars, nonaromatic amino acids, and organic acids. However, despite having a higher 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene copy number that could upregulate the phenylpropanoid metabolism, the nonstressed GR-biotypes were less abundant in specialized (secondary) metabolites. Under glyphosate stress, 80% of metabolites, including shikimate, that accumulated in GS-biotypes also increased in the GR-biotypes. However, glyphosate triggered the preferential accumulation of glycosides of dihydroxylated and methoxylated flavanols with higher antioxidant potential, and ferulic acid derivatives, specifically in GR-biotypes. The disruption of the shikimate pathway and the accumulation of phenylpropanoids upon glyphosate exposure suggest that the stress response of GR-biotypes could be partly induced. This differential response was less evident in other phytochemical classes and under drought, highlighting that the phytochemical responses are stress-specific rather than biotype-specific.