This study shows that Arabidopsis thaliana WRKY45 gene has an important role in limiting green peach aphid (GPA; Myzus persicae Sülzer) infestation. WRKY45 belongs to the WRKY family of transcription factors, which is one of the largest transcription factor family in plants. In response to GPA infestation, expression of WRKY45 was systemically upregulated in leaves and roots, with highest expression in the vascular tissues, which are the site of aphid feeding. GPA colonization was better on the wrky45 mutant compared to the wild-type (WT) plant. In contrast, GPA poorly colonized plants that were overexpressing (OE) WRKY45, thus confirming an important role for WRKY45 in plant defense to the GPA. A WRKY45-dependent process adversely impacted the reproductive rate of GPA and feeding from the sieve elements. RNA-seq experiments indicated a major impact of WRKY45 overexpression on expression of genes associated with dehydration and abscisic acid biosynthesis and signaling. In agreement with the RNA-seq data, ABA content was also higher in WRKY45-OE plants. However, genetic studies with an ABA-insensitive mutant (abi2-2) indicates that the WRKY45-OE conferred resistance to GPA is mediated through an ABA-independent mechanism. WRKY45-OE plants showed enhanced tolerance to drought and salt stresses. Genetic studies indicate that ABA signaling is critical for WRKY45's involvement in promoting plant tolerance to drought. Taken together, these results demonstrate that WRKY45 acts as a positive regulator of plant responses to GPA infestation, and drought and salt stress responses.