The objective was to determine differences in hindgut microbiome and metabolome in neonatal heifer calves retrospectively grouped as most feed-efficient (M-eff) or least feed-efficient (L-eff). Immediately after birth, 26 Holstein heifer calves were selected randomly for the study. Calves received 3.8 L of first-milking colostrum from the respective dam within 8 h after birth. Calves were housed in individual outdoor hutches bedded with straw, fed twice daily with a milk replacer, and had ad libitum access to a starter grain mix from birth to weaning at 42 d of age. Calves were classified into M-eff (n = 13; RFI coefficient = −0.17 +/−0.03 kg daily solid feed intake (FI)/d) and L-eff (n = 13; RFI coefficient = 0.17 +/−0.03 kg FI/d) based on a linear regression model involving FI, average daily gain (ADG), and metabolic body weight. Fecal samples were collected at d 0 (i.e., at birth before colostrum feeding), 14, 28, and 42 (before weaning) for microbiome and untargeted metabolome analyses using 16s rRNA gene sequencing and LC-MS. The MIXED procedure of SAS 9.4 was used for repeated measures analysis of body measurements, FI, and ADG. Both RFI groups and time (day or week) were considered as fixed factors in the model. Fecal microbiome data were analyzed with QIIME 2 and metabolome data with MetaboAnalyst 4.0. During the preweaning period, M-eff heifers had lower FI (P < 0.01) and cumulative fiber intake (P < 0.01) compared with L-eff heifers. However, no differences between groups were detected (P > 0.05) for body weight, ADG, wither height, hip height, and hip width. Fecal microbiome analysis revealed that M-eff calves had greater (P < 0.05) Proteobacteria, Succinivibrio, and Aeromonadales and lower (P < 0.05) Fusobacteria, Spirochaetia, and Lachnospiraceae. Furthermore, higher efficiency calves had favorable alterations in hindgut metabolome as indicated by upregulation (fold change > 2.0) of pathways associated with energy production (citric acid cycle), amino acid metabolism (tryptophan and phenylalanine) and vitamin metabolism (folate and biotin). Overall, results indicate greater feed efficiency in preweaned dairy heifers is associated with unique hindgut microbiome and metabolome profiles.