Prenatal valproic acid (VPA) exposure is strongly linked to developmental cardiotoxicity, yet no targeted pharmacological countermeasure exists. Converging mechanistic evidence indicates that VPA cardiotoxicity centers on AMPK/PGC-1α suppression, positioning the AMPK activator metformin (MET) as a rational candidate for in vivo protection. We examined MET’s protective effects against VPA-induced developmental cardiotoxicity in zebrafish embryos. Embryos were randomly allocated to four groups (Control, VPA 0.1 mM, MET 10 mM, VPA + MET) immediately after fertilization and chronically exposed until 96 hpf. Oxidative stress biomarkers (MDA, NO, SOD, GSH) and the expression of cardiac (nkx2.5, vmhc, amhc), AMPK (prkaa2, acaca), and mitochondrial/energy-related genes (ppargc1a, cpt1b, pck1, atp5pb, mt-nd1) were quantified. Compared with controls, VPA reduced nkx2.5 (p < 0.01) and elevated amhc (p < 0.05), triggered pericardial edema (p < 0.0001), suppressed prkaa2, ppargc1a, and atp5pb (p < 0.05, p < 0.001, and p < 0.0001, respectively), upregulated acaca (p < 0.0001), increased MDA and NO (p < 0.0001), and lowered SOD and GSH (p < 0.0001 and p < 0.001, respectively). Relative to the VPA group, MET co-treatment restored nkx2.5 expression (p < 0.001), attenuated pericardial edema (p < 0.0001), increased prkaa2 (p < 0.05), ppargc1a (p < 0.01), and atp5pb (p < 0.0001), suppressed acaca (p < 0.0001), and normalized MDA (p < 0.05), NO (p < 0.0001), SOD, and GSH (both p < 0.0001). The restoration of prkaa2/ppargc1a, mitochondrial, and antioxidant capacity by MET suggests that the AMPK/PGC-1α axis may serve as a central target in VPA cardiotoxicity.