This proof-of-concept study aimed to assess the optimal timing, dosing, and duration of vitamin C administration to increase survival and attenuate organ injuries in murine sepsis. Mice were randomized to receive ascorbic acid (AscA) at 1 or 6 h after cecal ligation and puncture (CLP). At each time point, mice randomly received AscA for 4 or 8 d. Mice were assigned to sham and CLP groups, as well as CLP + AscA groups that were treated with AscA at doses of 90, 180, or 360 mg/kg/d. The survival curves diverged significantly when AscA was injected at doses of 180 or 360 mg/kg/d for 8 d, although this was not observed when the treatment was limited to 4 d. AscA at doses of 180 or 360 mg/kg/d for 8 d preserved lung architecture while attenuating the abnormal expression of tight junction proteins. Kidney and liver injuries were evident in CLP mice, with elevated expression of biomarkers and inflammatory mediators; however, exposure to AscA at doses of 180 or 360 mg/kg/d for 8 d improved the histological changes and decreased biomarker expression levels. Very high-dose and prolonged vitamin C administration may potentially play a role in the management of sepsis-associated organ injuries.