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Background/Objectives: Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of neurodevelopmental diseases. In a previous retrospective study, we revealed that the levels of the soluble form of lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) are linked to HIE severity. We conducted a prospective investigation to evaluate the association between sLOX-1 levels and HIE severity using the Sarnat staging system, as well as a multicenter study to assess neurodevelopmental sequelae in the short term. Methods: A total of 193 infants were enrolled in the study between April 2018 and March 2021. We divided the infants into groups as follows: infants without HIE were assigned to a normal control group, and those with HIE to mild, moderate, and severe HIE groups. We measured 191 samples, excluding three participants. The distribution of 191 participants was as follows: 88 normal samples of 50 umbilical cord (UC) arteries and 38 venous blood samples (control; CTL), as well as 103 HIE samples of 34 mild, 55 moderate, and 14 severe HIE samples. All the plasma samples were collected until 6 h after birth. Results: The mean sLOX-1 value in the CTL group was 613 pg/mL (IQR: 474-925 pg/mL) and that in the UC group was 497 pg/mL (IQR: 337-693 pg/mL), with no significant difference (p = 0.136). The mean sLOX-1 value in the mild HIE group was 1030 pg/mL (IQR: 658-1547 pg/mL), 1026 pg/mL (IQR: 710-2051 pg/mL) in the moderate HIE group, and 1444 pg/mL (IQR: 766-3927 pg/mL) in the severe HIE group. There were significant differences between the CTL and HIE groups (p = 0.006) and between the CTL and mild HIE groups (p < 0.05), but not between the mild HIE and the moderate and severe HIE groups (p = 0.088). The other blood markers exhibited no correlation with Sarnat severity. Interestingly, blood sLOX-1 levels increased with Sarnat severity. Conclusions: The results of this study indicated that sLOX-1 level was correlated with Sarnat severity. Moreover, early assessment of sLOX-1 level may be useful for deciding whether to induce therapeutic hypothermia and/or other treatments, and sLOX-1 may serve as a short-term outcome biomarker of HIE.