Although saline is commonly used during cardiopulmonary resuscitation (CPR) or post-cardiac arrest care, it has detrimental effects. This trial aimed to evaluate the efficacy of a balanced crystalloid solution (Plasma Solution-A [PS]) in out-of-hospital cardiac arrest (OHCA) patients and compare it with the efficacy of saline. A randomized, unblinded clinical trial was conducted using PS and saline for intravenous fluid administration during CPR and post-cardiac arrest care of non-traumatic OHCA patients admitted to the emergency department of a tertiary university hospital. Patients received saline (saline group) or PS (PS group) within 24 h of hospital arrival. The primary outcomes were changes in arterial pH, bicarbonate, base excess (BE), and chloride levels within 24 h. The secondary outcomes were clinical outcomes including mortality. Of the 364 patients, data from 27 and 26 patients in the saline and PS groups, respectively, were analyzed. Analysis using a linear mixed model revealed a significant difference in BE change over time between the groups (treatment-by-time p = 0.044). Increase in BE and bicarbonate levels from 30 min to 2 h was significantly greater (p = 0.044 and p = 0.024, respectively) and the incidence of hyperchloremia was lower (p < 0.001) in the PS group than in the saline group. However, there was no difference in clinical outcomes. Use of PS for resuscitation resulted in a faster improvement in BE and bicarbonate, especially in the early phase of post-cardiac arrest care, and lower hyperchloremia incidence than the use of saline, without differences in clinical outcomes, in OHCA patients.