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Introduction: D-dimer is a marker of coagulation and fibrinolysis widely used in clinical practice for assessing thrombotic activity. While it is commonly ordered in the Emergency Department (ED) for suspected venous thromboembolism (VTE), elevated D-dimer levels can occur due to various other disorders. The aim of this study was to find out the causes of elevated D-dimer in patients presenting to a large ED in Saudi Arabia and evaluate the accuracy of D-dimer in diagnosing these conditions. Methods: Data was collected from an electronic hospital information system of patients who visited the ED from January 2016 to December 2022. Demographic information, comorbidities, D-dimer levels, and diagnoses were analyzed. Statistical analysis was performed using the SPSS software. The different diagnoses associated with D-dimer levels were analyzed by plotting the median D-dimer levels for each diagnosis category and their interquartile ranges (IQR). The receiver operating characteristic (ROC) curves were calculated and their area under the curve (AUC) values were demonstrated. The optimal cut-off points for specific diseases were determined based on the ROC analysis, along with their corresponding sensitivities and specificities. Results: A total of 19,258 patients with D-dimer results were included in the study. The mean age of the participants was 50 years with a standard deviation of ± 18. Of the patients, 66% were female and 21.2% were aged 65 or above. Additionally, 21% had diabetes mellitus, 20.4% were hypertensive, and 15.1% had been diagnosed with dyslipidemia. The median D-dimer levels varied across different diagnoses, with the highest level observed in aortic aneurysm 5.46 g/L. Pulmonary embolism (PE) and deep vein thrombosis (DVT) were found in 729 patients (3.8%) of our study population and their median D-dimer levels 3.07 g/L (IQR: 1.35–7.05 g/L) and 3.36 g/L (IQR: 1.06–8.38 g/L) respectively. On the other hand, 1767 patients (9.2%) were diagnosed with respiratory infections and 936 patients (4.9%) were diagnosed with shortness of breath (not specified) with median D-dimer levels of 0.76 g/L (IQR: 0.40–1.47 g/L) and 0.51 g/L (IQR: 0.29–1.06 g/L), respectively. D-dimer levels showed superior or excellent discrimination for PE (AUC = 0.844), leukemia (AUC = 0.848), and aortic aneurysm (AUC = 0.963). DVT and aortic dissection demonstrated acceptable discrimination, with AUC values of 0.795 and 0.737, respectively. D-dimer levels in respiratory infections and shortness of breath (not specified) exhibited poor to discriminatory performance. Conclusion: This is the first paper to identify multiple causes of elevated D-dimer levels in Saudi Arabia population within the ED and it clearly highlights their accurate and diagnostic values. These findings draw attention to the importance of considering the specific clinical context and utilizing additional diagnostic tools when evaluating patients with elevated D-dimer levels. [ABSTRACT FROM AUTHOR]