Background: Pentraxins (PTX) play key roles in innate immunity and inflammatory responses. An increase in PTX3 levels may be a marker of early radiation injury in the lung. Thus, we aimed to determine the effect of radiation on PTX3 expression in a lung injury mouse model. Materials and Methods: Twenty-four 6–8-week-old mice were divided into 4 groups, one control (group 1) and three experimental groups (groups 2–4) irradiated with 6 MV photons and 5 Gy in a single fraction. Groups 2, 3, and 4 were sedated and euthanized 24, 72, and 168 h after radiation, respectively. The right lung middle lobe was then removed for histochemical examination and immunostaining for PTX3 expression, which was evaluated semi-quantitatively using H-SCORE analysis. Kolmogorov-Smirnov and Kruskal Wallis one-way analysis of variance were used for statistical analysis. Results: Immunohistochemistry of lung tissue samples showed different PTX3 expression levels across the four groups. Group 1 showed weak staining (232.50 ± 9.501), while group 2 (301.50 ± 7.472) and group 3 (283.50 ± 7.090) showed strong immunoreactivity. Group 4 showed moderate PTX3 immunoreactivity (271.50 ± 10.013). Moreover, H-score values between control and early radiation groups were statistically significant (group 1 vs. group 2, p < 0.001; group 1 vs. group 3, p = 0.002). Conclusion: PTX3 levels may be an early marker for long-term radiation effects. Our study provides insights into the pathological processes of pulmonary inflammation and acute radiation injury, and may provide novel therapeutic strategies for controlling pulmonary inflammation without eliciting radiation injury.