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Simple Summary: Although gastrointestinal stromal tumor (GIST) is a relatively rare mesenchymal neoplasm of the digestive tract, molecular advancements in GISTs over the past two decades have caused a paradigm shift in the field of precision oncology. GISTs are mainly driven by activating mutations in the KIT or PDGFRA oncogenes, rendering them sensitive to targeted therapies. However, there is a significant lack of data from Kuwait that needs to be addressed. We carried out this retrospective analysis of a cohort of 200 GIST patients at the Kuwait Cancer Center to provide much-needed insights into the genetic makeup and clinicopathological characteristics of our population. We detailed the mutational spectrum in KIT and PDGFRA, identified a small subgroup of wild-type tumors, and shed some light on the clinical implications. This study opens the doors for potential larger-scale, multi-institutional outcome studies in the Arabian Gulf region. In gastrointestinal stromal tumors (GISTs), identifying prototypical mutations in the KIT/PDGFRA oncogenes, or in rare alternate genes, is essential for prognostication and predicting response to tyrosine kinase inhibitors. Conversely, wild-type GISTs (WT-GIST), which lack known mutations, have limited treatment options. Data on the mutational landscape of GISTs and their impact on disease progression are very limited in Kuwait. Using a targeted next-generation sequencing panel, we investigated the spectrum and frequency of KIT, PDGFRA, and RAS-pathway-related mutations in 95 out of 200 GISTs diagnosed at Kuwait Cancer Center from 2005 to 2023 and assessed their correlation with clinicopathological parameters. Among the 200 tumors (median age 55 years; 15–91), 54% originated in the stomach, 33% in the small bowel, 7% in the colorectum, 1.5% in the peritoneum, and 4.5% had an unknown primary site. Of the 95 molecularly profiled cases, 88% had a mutation: KIT (61%), PDGFRA (25%), NF1 (2%), and one NTRK1 rearrangement. Ten WT-GISTs were identified (stomach = 6, small bowel = 2, and colorectum = 2). WT-GISTs tended to be smaller (median 4.0 cm; 0.5–8.0) (p = 0.018), with mitosis ≤5/5 mm2, and were of lower risk (p = 0.019). KIT mutations were an adverse indicator of disease progression (p = 0.049), while wild-type status did not significantly impact progression (p = 0.934). The genetic landscape in this cohort mirrors that of global studies, but regional collaborations are needed to correlate outcomes with genetic variants. [ABSTRACT FROM AUTHOR]