The 1.6 Mb 3q29 deletion is associated with developmental and psychiatric phenotypes, including a 40-fold increased risk for schizophrenia. Reduced birth weight and a high prevalence of feeding disorders in patients suggest underlying metabolic dysregulation. We investigated 3q29 deletion-induced metabolic changes using our previously generated heterozygous B6.Del16 mouse model. Animals were provided either standard chow (STD) or high-fat diet (HFD). Growth curves were performed on HFD mice to assess weight change (n = 30-50/group). Indirect calorimetry and untargeted metabolomics were performed on STD and HFD mice to evaluate metabolic phenotypes (n = 8-14/group). A behavioral battery was performed on STD and HFD mice to assess behavior change after the HFD challenge (n = 5-13/group). We found that B6.Del16 animals preferentially use dietary lipids as an energy source. Untargeted metabolomics of liver tissue showed a strong sex-dependent effect of the 3q29 deletion on fat metabolism. A HFD partially rescued the 3q29 deletion-associated weight deficit in females, but not males. Untargeted metabolomics of liver tissue after HFD revealed persistent fat metabolism alterations in females. The HFD did not affect B6.Del16 behavioral phenotypes, suggesting that 3q29 deletion-associated metabolic and behavioral outcomes are uncoupled. Our data suggest that dietary interventions to improve weight phenotypes in 3q29 deletion syndrome patients are unlikely to exacerbate behavioral manifestations. Our study also highlights the importance of assessing sex in metabolic studies and suggests that mechanisms underlying 3q29 deletion-associated metabolic phenotypes are sex-specific.