Background: Evidence suggests that fluctuations of cortisol and physiological parameters can emerge during the course of mild Traumatic Brain Injury (mTBI). Objective: To investigate fluctuations of cortisol and physiological parameters during the acute phase of mTBI in hospitalized patients. Methods: 30 participants (19 patients with mTBI and 11 controls) were examined for saliva cortisol dynamics, heart rate (HR), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP) and body temperature (BT) fluctuations for four consecutive days. Also, the participants completed the Athens Insomnia Scale and Epworth Sleepiness Scales, in order to check for sleep problems. Results: Patients showed elevated levels of cortisol relative to controls (peak at 8 am and lowest levels at 12 am), as well as for most physiological parameters. MAP was significantly higher for patients throughout the measurement period, and BT was elevated for patients relative to controls at almost all measurements of the first and second day. Mean HR tended to track at non-significantly higher levels for the mTBI group. Patients’ sleepiness and insomnia values (ESS and AIS) were initially significantly higher relative to controls but the difference dissipated by day 4. Conclusion: The increase in absolute values of cortisol and physiological parameters measurements, indicates that in the acute phase of mTBI, a stressful process is activated which may affect sleep quality as well. Supplemental data for this article is available online at at doi: 10.1080/00207454.2021.1951264