D-dimer assay’s utility for excluding venous thromboembolism (VTE) in hospitalized patients is debatable. We aimed to assess the current use of D-dimer as a diagnostic tool for excluding VTE in hospitalized patients and examine a mandatory age-adjusted D-dimer (AADD) threshold for diagnostic imaging. Retrospective cohort study between 2014 to 2019 that included patients from medical and surgical wards with a positive AADD result drawn during their hospitalization. The outcomes were determining a D-dimer threshold requiring further evaluation and assessing the prognostic value of D-dimer in predicting clinically relevant VTE in hospitalized patients. The cohort included 354 patients, 56% of them underwent definitive diagnostic imaging, and 7.6% were diagnosed with VTE after a positive AADD within 90 days of follow-up. Mortality rates were higher in patients diagnosed with VTE (33.3% vs. 15.9%, p = 0.03). Patients with pneumonia and other infectious etiologies were less likely to be further evaluated by definitive imaging (p = 0.001). Patients with a respiratory complaint (p = 0.02), chest pain (p < 0.001), or leg swelling (p = 0.01) were more likely to undergo diagnostic imaging. Patients with D-dimer levels > X2 the AADD were at increased risk of VTE [OR 3.87 (1.45–10.27)]. At 90 days of follow-up, no excess mortality was observed for patients without diagnostic evaluation following elevated AADD. D-dimer may be used in hospitalized patients to exclude VTE using the traditional AADD thresholds, with a high negative predictive value. D-dimer levels > X2 the AADD usually mandates further diagnostic imaging, while lower levels, probably do not require additional workup, with a sensitivity of almost 80% and no excess mortality.