Background/objectives: There is a growing appreciation for individual responses to diet. In a previous study, mouse strain-specific responses to American and ketogenic diets were observed. In this study, we searched for genetic variants underlying differences in the responses to American and ketogenic diets between C57BL/6J (B6) and FVB/NJ (FVB) mouse strains. Results: Genetic mapping of fat and lean mass gain revealed QTLs on Chromosome (Chr) 1 at 191.6 Mb (Fmgq1) (P < 0.001, CI = 180.2–194.4 Mb), Chr5 at 73.7 Mb (Fmgq2, Lmgq1) (P < 0.001, CI = 66.1–76.6 Mb), and Chr7 at 40.5 Mb (Fmgq3) (P < 0.01, CI = 36.6–44.5 Mb). Analysis of serum HDL cholesterol concentration identified a significant (P < 0.001, CI = 160.6–176.1 Mb) QTL on Chr1 at 168.6 Mb (Hdlq1). Causal network inference suggests that HDL cholesterol and fat mass gain are both linked to Fmgq1. Conclusions: Strong sex effects were identified at both Fmgq2 and Lmgq1, which are also diet-dependent. Interestingly, Fmgq2 and Fmgq3 affect fat gain directly, while Fmgq1 influences fat gain directly and via an intermediate change in serum cholesterol. These results demonstrate how precision nutrition will be advanced through the integration of genetic variation and sex in physiological responses to diets varied in carbohydrate composition.