The present study was carried out with the aim of (i) evaluating the effect of chitosan (CTS) on the growth of durum wheat under salinity and (ii) examining CTS-regulated mechanisms of salinity tolerance associated with the antioxidant defense system. To achieve these goals, durum wheat seedlings were treated with CTS at different molecular weight, low (L-CTS, 50–190 kDa), medium (M-CTS, 190–310 kDa) and high (H-CTS, 310–375 kDa). The results obtained show that exposure to 200 mM NaCl reduced the shoot and the root dried biomass by 38% and 59%, respectively. The growth impairment induced by salinity was strongly correlated with an increase in the superoxide anion production (5-fold), hydrogen peroxide content (2-fold) and malondialdehyde (MDA) content (4-fold). Seedlings responded to the oxidative stress triggered by salinity with an increase in the total phenolic content (TPC), total flavonoid content (TFC) and total antioxidant activity (TAA) by 67%, 51% and 32%, respectively. A salt-induced increase in the activity of the antioxidant enzymes superoxide dismutase and catalase (CAT) of 89% and 86%, respectively, was also observed. Treatment of salt-stressed seedlings with exogenous CTS significantly promoted seedling growth, with the strongest effects observed for L-CTS and M-CTS, which increased the shoot biomass of stressed seedlings by 32% and 44%, respectively, whereas the root dried biomass increased by 87% and 64%, respectively. L-CTS and M-CTS treatments also decreased the superoxide anion production (57% and 59%, respectively), the hydrogen peroxide content (35% and 38%, respectively) and the MDA content (48% and 56%, respectively) and increased the TPC (23% and 14%, respectively), the TFC (19% and 10%, respectively), the TAA (up to 10% and 7%, respectively) and the CAT activity (29% and 20%, respectively). Overall, our findings indicate that CTS exerts its protective role against the oxidative damages induced by salinity by enhancing the antioxidant defense system. L-CTS and M-CTS were the most effective in alleviating the adverse effect of NaCl, thus demonstrating that the CTS action is strictly related to its molecular weight.