The aim of our study was to compare brain tissue net water uptake (NWU), cerebral oxygenation, and microcirculation changes in perilesional penumbra foci (PPF) in moderate isolated traumatic brain injury (moiTBI) patients. Materials and Methods: 77 moiTBI patients (women 35; men 42, age 37 years [34;39]) with unilateral frontal/frontotemporal lesions (Marshall II-III) were included in this retrospective, non-randomized, single-center study. Perfusion parameters were measured in PPF zones and determined using multiphase perfusion computed tomography (PCT) in the first 2 days after trauma and admission. NWU in hypoattenuated perilesional zones was calculated using non-contrast CT. Cerebral oxygenation (SctO2) was simultaneously measured using near-infrared spectroscopy in the frontal lobes with PCT. Data are shown as a median [interquartile range]. Statistical analysis was performed using nonparametric statistics. P < 0.05 was considered statistically significant. Results: In PPF, SctO2 was 64.03% [60.1;67.0], cerebral blood flow (CBF) was 30.6 ml/100 g/min [22.3; 38.7], cerebral blood volume (CBV) was 2 ml/100 g [1.6; 2.5], mean transit time (MTT) was 4.8 s [4.1;5.8], time to peak (TTP) was 21.8 s [20;24.2], NWU was 4.98% [2.21;7.39]. CBF, CBV, and SctO2 in PPF were significantly lower; MTT was more prolonged than in non-damaged tissue (p < 0.001). Increased NWU values in PPF were significantly correlated with CBV (r = 0.723, p < 0.001); CBF (r = −0.228, p = 0.048), TTP (r 0.225, p = 0.047), and SctO2 (r = −0.608, p < 0.001). There were no significant correlations between NWUPPF and MTT. Conclusions: Brain edema in PPF was significantly associated with cerebral microcirculation and cerebral O2 saturation disturbances in moiTBI.