The aims of this study were to observe the effects of vacuum sealing drainage (VSD) with three different negative pressures on the wound healing rate, macrophage count and the expression of hyaluronic acid (HA) as well as its receptor CD44 in seawater-immersed blast-injury wounds (SIBIW) and to determine the optimal negative pressure value. In a minipig SIBIW model, different suction pressures and routine dressing were applied. Histological and immunohistochemical comparisons as well as molecular biology methods were performed to compare the wound healing conditions, macrophage count and the levels of HA and CD44. The wound healing rate of the VSD group was significantly higher than that of the control group, with the -120 mmHg group exhibiting the best effects. The macrophage count of the VSD group was higher than that of the control group. The HA level fluctuation was higher in the VSD group, with the -120 mmHg and the -180 mmHg groups showing the most significant fluctuation (P < 005). CD44 was expressed in the full-thickness wound-limbic tissues and was higher in the treatment group than that in the control group, with the -120 mmHg group having the most obvious expression. VSD significantly improved the healing ability and increased the macrophage count and the HA content. It also promoted CD44 expression. -120 mmHg is the optimal negative pressure value.