Waterhemp [Amaranthus tuberculatus (Moq.) Sauer] is one of the most troublesome weeds in the United States. An A. tuberculatus population (CHR) was identified in Illinois, USA, as resistant to herbicides from six different site-of-action groups. Recently, the same population was also recognized as dicamba resistant. This study aimed to identify key resistance genes and the putative dicamba resistance mechanism in A. tuberculatus via transcriptomics analysis. Multiple differentially expressed (DE) genes and co-expression gene modules were identified as associated with dicamba resistance. Specifically, genes encoding glutathione S-transferases (GSTs), ATP-binding cassette transporters, peroxidases, and uridine diphosphate (UDP)glycosyltransferases (UGTs) were identified. Results indicated enhanced oxidative stress tolerance as the primary mechanism for reducing dicamba toxicity. Results also point to potential glycosylation via UGTs and conjugation via GSTs of dicamba and its by-products. This is the first transcriptomics characterization of dicamba resistance in A. tuberculatus. Multiple non-target-site resistance genes were identified, indicating a cross-resistance pattern in the CHR population leading to a putative-enhanced oxidative stress response. Regions of multiple DE genes (i.e., genomic hot spots) across the A. tuberculatus genome corroborate previous results and potentially add to the complexity of non-target-site resistance traits.