Background <p>In premature newborn infants, preterm white matter injury (PWMI) causes motor and cognitive disabilities. Accumulating evidence suggests that PWMI may result from defected differentiation of oligodendrocyte precursor cells (OPCs) and impaired maturation of oligodendrocytes. However, the underlying mechanisms remain unclear.</p> Methods <p>Using RNAscope, we analyzed the expression level of RNA-binding protein LIN28A in individual OPCs. Knockout of one or both alleles of <i>Lin28a</i> in OPCs was achieved by administrating tamoxifen to NG2^CreER::Ai14::Lin28a^flox/+ or NG2^CreER::Ai14::Lin28a^flox/flox mice. Lentivirus expressing FLEX-<i>Lin28a</i> was used in NG2^CreER mice to overexpress LIN28A in OPCs. A series of behavioral tests were performed to assess the cognitive functions of mice. Two-tailed unpaired t-tests was carried out for statistical analysis between groups.</p> Results <p>We found that the expression of <i>Lin28a</i> was decreased in OPCs in a PWMI mouse model. Knockout of one or both alleles of <i>Lin28a</i> in OPCs postnatally resulted in reduced OPC differentiation, decreased myelinogenesis and impaired cognitive functions. Supplementing LIN28A in OPCs postnatally was able to promote OPC differentiation and enhance myelinogenesis, thus rescuing the cognitive functions in PWMI mice.</p> Conclusion <p>Our study reveals that LIN28A is critical in regulating postnatal myelinogenesis. Overexpression of LIN28A in OPCs rescues cognitive deficits in PWMI mice by promoting myelinogenesis, thus providing a potential strategy for the treatment of PWMI.</p>