Sesame is a source of a healthy vegetable oil, attracting a growing interest worldwide. Abiotic stresses have devastating effects on sesame yield; hence, studies have been performed to understand sesame molecular responses to abiotic stresses, but the core abiotic stress-responsive genes (CARG) that the plant reuses in response to an array of environmental stresses are unknown. We performed a meta-analysis of 72 RNA-Seq datasets from drought, waterlogging, salt and osmotic stresses and identified 543 genes constantly and differentially expressed in response to all stresses, representing the sesame CARG. Weighted gene co-expression network analysis of the CARG revealed three functional modules controlled by key transcription factors. Except for salt stress, the modules were positively correlated with the abiotic stresses. Network topology of the modules showed several hub genes predicted to play prominent functions. As proof of concept, we generated over-expressing Arabidopsis lines with hub and non-hub genes. Transgenic plants performed better under drought, waterlogging, and osmotic stresses than the wild-type plants but did not tolerate the salt treatment. As expected, the hub gene was significantly more potent than the non-hub gene. Overall, we discovered several novel candidate genes, which will fuel investigations on plant responses to multiple abiotic stresses.