In this study, LRCF, a long noncoding RNA (lncRNA) related to cognitive function, which was first discovered and named by our group, was shown to be involved in the propofol-induced proliferation and apoptosis of oligodendrocytes (OLGs). Our systematic study showed that LRCF expression differs in OLGs of mice of different ages. We found that neonatal mice with a high level of LRCF typically showed greater propofol-induced injury of OLGs. Mechanistic research has shown that LRCF can block the HIF-1α/miR138-5p/Caspase-3 pathway by binding to miR138-5p to form a microRNA (miRNA) sponge and result in cell damage through HIF-1α/Caspase-3 pathway in propofol induced OLGs. This may be the intrinsic reason why neonatal animals with high levels of LRCF tend to develop learning disability and neuro-degeneration more frequently than adults’ after exposure to general anesthesia. When LRCF is highly expressed, HIF-1α directly regulates the transcription of the Caspase-3 gene by binding to the transcription factor binding site (TFBS) in its promoter, which induces OLGs apoptosis. LRCF is crucial for the mutual activation of the HIF-1α/miR138-5p/Caspase-3 OLGs survival pathway and the HIF-1α/Caspase-3 OLGs damage pathway. This study is the first to report that up-regulation of HIF-1α in OLGs treated with Propofol can promote apoptosis through HIF-1α/caspase-3 pathway and resist apoptosis through HIF-1α/miR-138-5p/caspase-3 pathway. The effect of HIF-1α on Caspase-3 expression depends on LRCF expression, which provides important theoretical support for gene therapy targeting LRCF. The further significance of this study is points to an involvement of the genetic background with high LRCF expression may serve as an important marker for identifying patients with a high risk of OLGs injury by Propofol. Thus, caution should be taken when administrating propofol in these patients, especially pediatric patients with high level of LRCF.