We hypothesized that different combinations of initial and target temperatures during targeted temperature management (TTM) may be associated with neurological outcomes in out-of-hospital cardiac arrest (OHCA) survivors. Adult patients with OHCA who underwent TTM were enrolled. The study participants were divided into four groups: lower initial body temperature and lower target temperature (Low-Low group), lower initial body temperature and higher target temperature (Low-High group), higher initial body temperature and lower target temperature (High-Low group), and higher initial body temperature and higher target temperature (High-High group). Initial body temperature was dichotomized based on the median value (35.6 ◦C) as a cutoff, and the target temperature was dichotomized with a target temperature of 34 ◦C as a cutoff. The primary outcome was defined as a favorable 28-day neurological outcome. In total, 231 patients were included in the analysis, and 74 (32.0%), 43 (18.6%), 82 (35.5%), and 32 (13.9%) patients were classified into the Low-Low, Low-High, High-Low, and High-High groups, respectively. The proportion of patients with favorable 28-day neurological outcomes differed among the study groups (Low-Low, 14 (18.9%); Low-High, 7 (16.3%); High-Low, 37 (45.1%); High-High, 11 (34.4%); p = 0.001). In the multivariable analysis, the Low-High group was independently associated with a less favorable 28-day neurological outcome compared to the High-Low group (adjusted odds ratio, 0.22; 95% confidence interval, 0.06–0.91; p = 0.036). In conclusion, higher initial body temperature and lower target temperature during TTM were independently associated with a more favorable 28-day neurological outcome compared to the lower initial body temperature and higher target temperature in patients resuscitated from OHCA of medical etiology.