Prescription opioid abuse during and after pregnancy is a rising public health concern. While earlier studies have documented that offspring exposed to opioids in utero have impaired neurodevelopment, a significant knowledge gap remains in comparing the overall development between offspring exposed in utero and postnatally. Adding a layer of complexity is the role of heredity in the overall development of these exposed offspring. To fill in these important knowledge gaps, the current study uses a preclinical rat model mimicking oxycodone (oxy) exposure in utero (IUO) and postnatally (PNO) to investigate comparative and intergenerational effects in the two different treatment groups. While significant phenotypic attributes were observed with the two treatments and across the two generations, RNA sequencing revealed alterations in the expression of key synaptic genes in the two exposed groups in both generations. RNA sequencing and post validation of genes using RT-PCR highlighted the differential expression of several neuropeptides associated with the hypocretin system, a system recently implicated in addiction. Further, behavior studies revealed anxiety-like behaviors and social deficits that persisted even in the subsequent generations in the two treatment groups. To summarize, our study for the first time reveals a new line of investigation on the potential risks associated with oxy use during and after pregnancy, specifically the disruption of neurodevelopment and intergenerational impact on behavior.