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The perinatal period is a critical window for neurodevelopment, during which the brain is especially vulnerable to environmental factors that can disrupt typical developmental processes. It is understood that maternal infection is an environmental factor that can contribute to altered brain development in the offspring, which can result in developmental abnormalities in the prefrontal cortex (PFC), as well as an inhibition of sensorimotor abilities. Another environmental factor that may disrupt brain development is exposure to phthalates, which are endocrine-disrupting plasticizing agents that we absorb from several sources in our environment. While both environmental factors have been shown to alter development of the PFC, evidence suggests that phthalates can influence and interact with the immune response, perhaps exacerbating the effects of either exposure alone. The present research aimed to measure the combined effects of maternal infection via lipopolysaccharides (LPS) and exposure to an environmentally relevant mixture of phthalates on the number of neurons and glia in the rat medial prefrontal cortex (mPFC), mPFC volume, and performance on a sensorimotor test. While we did not see an effect of treatments on sensorimotor gating behavior, there were multiple neuroanatomical effects. Stereological analysis of offspring’s brain tissue revealed that at P10, LPS decreased neuron density in the mPFC. At P60, LPS reduced mPFC volume, cortical thickness, the number of neurons, and the volume of white matter volume. Phthalates reduced the density, but not total number of mPFC neurons. Additionally, we found a significant interaction between LPS and phthalates on the number of glial cells in young adulthood. These results have important implications for psychiatric disorders, including schizophrenia and ADHD.