There is evidence of the role of milk components in the metabolic programming of offspring. Here, we aimed to investigate the effects of a diet during lactation on breast milk leptin, adiponectin, and related miRNAs’ expression, and their impact on dams and their offspring. Dams were fed a control diet (controls) or a diet enriched with oleic acid, betaine, and leucine (TX) throughout lactation. A TX diet promoted higher leptin at lactation day (LD) five and lower adiponectin on LD15 (vs. controls) in milk, resulting in increased leptin to adiponectin (L/A) ratio throughout lactation. Moreover, TX diet reduced milk levels of miR-27a, miR-103, miR-200a, and miR-222. Concerning TX offspring, higher body fat was early observed and maintained into adult life, accompanied by higher HOMA-IR than controls at three months of age. Offspring body fat content in adulthood correlated positively with milk L/A ratio at LD15 and negatively with miRNAs modulated by the TX diet. In conclusion, maternal diet during lactation can modulate leptin and adiponectin interplay with miRNAs in milk, setting up the metabolic programming of the offspring. Better knowledge about the influence of diet on this process is necessary to promote a healthy adult life in the progeny.