Patients with metastatic bone disease (MBD) are at increased risk for venous thromboembolism (VTE) following orthopaedic surgery. Platelets are critical for thrombus formation, and increasing evidence suggests that the interplay between platelets and inflammation may promote this process. However, in patients with MBD, the extent and duration of post-operative hypercoagulability is poorly understood, and the pathophysiology of VTE in this population remains unknown. We aimed to address these knowledge gaps, and hypothesized that VTE would be associated with hypercoagulability, platelet activation and procoagulation, and elevated concentrations of circulating pro-inflammatory mediators. These hypotheses were tested in 35 patients with pathologic fractures due to MBD who required orthopaedic surgery. Study participants underwent serial phlebotomy over a 6-month post-operative period. Samples were analyzed using thrombelastography (TEG), TEG-based PlateletMapping®, and multiplex immunoassay analyses to quantify the extent and duration of hypercoagulability, platelet receptor pathway activity, and systemic inflammation. For population-specific insight, three subgroup analyses were performed. The 35-participant MBD cohort was dichotomized according to VTE incidence (yes/no) for the first analysis, and then by pathologic fracture type (acute/impending). The third subgroup analysis compared participants with acute hip fractures according to the presence of malignancy (MBD/non-cancer) using a subgroup of 10 participants from the overall MBD cohort, and a subgroup of 10 sex-matched participants without cancer. An additional sub-study was performed in 19 participants from the overall MBD cohort that used high-resolution fluorescence microscopy to visualize the platelet membrane and quantify platelet activation and procoagulation. Findings from this multi-modal study demonstrated that hypercoagulability, platelet receptor pathway hyperactivity, and systemic inflammation were elevated pre-operatively in participants who later developed VTE. This suggests that individuals at high VTE risk can be identified pre-operatively. Additionally, the results of subgroup analyses revealed that participants in the MBD and acute pathologic fracture subgroups were more hypercoagulable than participants in the non-cancer and impending fracture subgroups. Associations between hypercoagulability, platelet activation, and inflammation were observed in patients with MBD, with temporal change in each parameter mirroring the others throughout the study. Therefore, further investigation into platelet- and inflammation-mediated hypercoagulability may uncover novel and/or optimal targets for thromboprophylaxis for patients with MBD.