Background <p>While maternal obesity is a well-established risk factor for adverse fetal outcomes, the impact of pre-pregnancy underweight remains incompletely characterized. This study aimed to investigate the association between maternal pre-pregnancy underweight and fetal growth restriction (FGR) and, more critically, to elucidate the underlying mechanisms.</p> Methods <p>We conducted a retrospective cohort study of 7,504 singleton deliveries at a tertiary obstetric and gynecology hospital in Shanghai. Genome-wide DNA methylation profiling (using GM-seq, a bisulfite-free genomic methylation sequencing approach) and transcriptomic analysis (via RNA-seq) were conducted on placental samples obtained from FGR cases (<i>n</i> = 5) and healthy controls (<i>n</i> = 4).</p> Results <p>A significant dose-dependent association was observed between maternal pre-conception underweight (BMI (body mass index) &lt; 18.5&#xa0;kg/m²) and FGR, with an aOR (adjusted odds ratio) of 1.57 (95% confidence interval (CI): 1.31–1.88; <i>p</i> value &lt; 0.001). We identified 128 DMRs (differentially methylated regions) specifically associated with FGR in the context of maternal pre-pregnancy underweight. Notably, expression levels of two DMR-associated genes <i>TSTD1</i> and <i>KCNG2</i>, which are implicated in placental energy metabolism, were significantly dysregulated in FGR placentas from underweight mothers.</p> Conclusions <p>These results demonstrated that DNA methylation and transcriptional alterations of genes involved in placental energy metabolism may link maternal pre-pregnancy underweight to FGR. Thus, our findings highlighted the importance of pre-conception nutritional interventions to optimize fetal development.</p>