Cassava mosaic disease (CMD) is caused by viruses such as Sri Lankan cassava mosaic virus (SLCMV). It poses a significant threat to the cassava (Manihot esculenta) yield in Southeast Asia. Here, we investigated the expression of WRKY transcription factors (TFs) in SLCMV-infected cassava cultivars KU 50 (tolerant) and R 11 (susceptible) at 21, 32, and 67 days post-inoculation (dpi), representing the early, middle/recovery, and late infection stages, respectively. The 34 identified WRKYs were classified into the following six groups based on the functions of their homologs in the model plant Arabidopsis thaliana (AtWRKYs): plant defense; plant development; hormone signaling (abscisic, salicylic, and jasmonic acid); reactive oxygen species production; basal immune mechanisms; and other related hormones, metabolites, and abiotic stress responses. Regarding the protein interactions of the identified WRKYs, based on the interactions of their homologs (AtWRKYs), WRKYs increased reactive oxygen species production, leading to salicylic acid accumulation and systemic acquired resistance (SAR) against SLCMV. Additionally, some WRKYs were involved in defense-related mitogen-activated protein kinase signaling and abiotic stress responses. Furthermore, crosstalk among WRKYs reflected the robustly restricted viral multiplication in the tolerant cultivar, contributing to CMD recovery. This study highlights the crucial roles of WRKYs in transcriptional reprogramming, innate immunity, and responses to geminivirus infections in cassava, providing valuable insights to enhance disease resistance in cassava and, potentially, other crops.