It is well-accepted that maternal obesity affects fetal development to elevate the risk of offspring disease, but how this happens is unclear. Understanding placental alterations during gestation as a consequence of maternal obesity is critical to understanding the impact of maternal obesity on fetal programming. Here, we used histological criteria, flow cytometry, quantitative PCR, and multiplex cytokine assays to examine changes in cell proliferation and inflammation in the placenta during gestation in a mouse model of maternal high-fat diet-induced obesity. We focused on mouse mid- to late gestation (approximately human late first and third trimester) because previous literature has indicated that this is when important regulators of metabolism, including that of the brain and endocrine pancreas, are forming. These studies were undertaken in order to understand how maternal obesity changes the placenta during this period, which might suggest a causal link to later-life metabolic dysfunction. We found that labyrinth thickness and cell proliferation were decreased at both pregnancy stages in obese compared to normal weight pregnancies. Inflammation was also altered in late pregnancy with increased macrophage activation and elevated cytokine gene expression in the placenta as well as increased abundance of some cytokines in the fetal circulation in obese compared to normal weight pregnancies. These changes in macrophage activation and cytokine gene expression were of greater magnitude and significance in placentas accompanying male fetuses. These data provide insight into placental changes in obesity and identify potential links between placental inflammation and programming of offspring disease by maternal obesity.