Background: The pathophysiological understanding of the inflammatory response in necrotizing soft-tissue infection (NSTI) and its impact on clinical progression and outcomes are not resolved. Hyperbaric oxygen (HBO₂) treatment serves as an adjunctive treatment; however, its immunomodulatory effects in the treatment of NSTI remains unknown. Accordingly, we evaluated fluctuations in inflammatory markers during courses of HBO₂ treatment and assessed the overall inflammatory response during the first 3 days after admission. Methods: In 242 patients with NSTI, we measured plasma TNF-α, IL-1β, IL-6, IL-10, and granulocyte colony-stimulating factor (G-CSF) upon admission and daily for three days, and before/after HBO² in the 209 patients recieving HBO². We assessed the severity of disease by Simplified Acute Physiology Score (SAPS) II, SOFA score, and blood lactate. Results: In paired analyses, HBO₂ treatment was associated with a decrease in IL-6 in patients with Group A-Streptococcus NSTI (first HBO₂ treatment, median difference −29.5 pg/ml; second HBO₂ treatment, median difference −7.6 pg/ml), and overall a decrease in G-CSF (first HBO₂ treatment, median difference −22.5 pg/ml; 2⁻ HBO₂ treatment, median difference −20.4 pg/ml). Patients presenting with shock had significantly higher baseline cytokines values compared to non-shock patients (TNF-α: 51.9 vs. 23.6, IL-1β: 1.39 vs 0.61, IL-6: 542.9 vs. 57.5, IL-10: 21.7 vs. 3.3 and G-CSF: 246.3 vs. 11.8 pg/ml; all p < 0.001). Longitudinal analyses demonstrated higher concentrations in septic shock patients and those receiving renal-replacement therapy. All cytokines were significantly correlated to SAPS II, SOFA score, and blood lactate. In adjusted analysis, high baseline G-CSF was associated with 30-day mortality (OR 2.83, 95% CI: 1.01–8.00, p = 0.047). Conclusion: In patients with NSTI, HBO₂ treatment may induce immunomodulatory effects by decreasing plasma G-CSF and IL-6. High levels of inflammatory markers were associated with disease severity, whereas high baseline G-CSF was associated with increased 30-day mortality.