Background Venous thromboembolism (VTE) is a common and potentially life-threatening complication in patients with lower limb traumatic fractures. Orthopaedic patients who experience trauma in the lower limbs with prolonged immobilization may experience a hypercoagulable state, which could eventually lead to the development of VTE. Therefore, this study aims to evaluate the changes in hypercoagulable markers, including haemostatic, inflammatory, and haematological biomarkers in orthopaedic trauma patients with prolonged immobilization. Materials/method This prospective cohort study was conducted at Hospital Universiti Sains Malaysia from August 2020 to March 2022. Every patient with fractures in the lower limbs was screened for eligibility, and patients who required immobilization for more than five days without receiving anticoagulant prophylaxis were recruited for this study. The laboratory tests, including D-dimer, fibrinogen, prothrombin time (PT), activated partial thromboplastin time (aPTT), erythrocyte sedimentation rate (ESR), and platelet count, were serially measured on day one and day five of hospitalization. The biomarkers were analyzed using a paired t-test, with a p-value <0.05 as a significant result. Results A total of 54 patients with fractures in the lower limbs, ages ranging from 12 to 50 years old, were involved in this study. The paired t-test analysis demonstrated that several biomarkers showed a significant increase in mean difference between day one and day five of immobilization, which included fibrinogen, ESR, and platelet count. The mean differences for each biomarker with fibrinogen were 0.66 g/L (p<0.001, 95% CI of mean difference: -1.04, -0.27), ESR increased by 17.98mm/hr (p<0.001, 95% CI of mean difference: -24.69, -11.27), and platelet count increased by 128.59×109/L (p<0.001, 95% CI of mean difference: -166.55, -90.64) on day five of immobilization. D-dimer was elevated in all patients on both post-trauma days; however, no significant difference was observed in this biomarker between day one and day five of immobilization. Conclusion In conclusion, our study found that fibrinogen, ESR, and platelet count levels were significantly increased in orthopaedic trauma patients with prolonged immobilization. The increase in these biomarkers indicates the body's reaction to tissue injury after trauma, which may contribute to the hypercoagulable states. Further research with a larger sample size is warranted to assess the viability of these biomarkers as potential diagnostic indicators for the development of VTE related to hypercoagulability.