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This study aimed to investigate the transgenerational effects of tributyltin exposure on rat neurodevelopment in male offspring and the potential mechanisms. Neonatal female rats were exposed to the environmental level of tributyltin and then mated with nonexposed males after sexual maturity to produce the F1 generation. The F1 generation (with primordial germ cell exposure) was mated with nonexposed males to produce nonexposed offspring (the F2 and F3 generations). Neurodevelopmental indicators and behavior were observed for the F1, F2, and F3 generations during postnatal days 1–25 and 35–56, respectively. We found premature eye-opening and delayed visual positioning in newborn F1 rats and anxiety and cognitive deficits in prepubertal F1 male rats. These neurodevelopmental impacts were also observed in F2 and F3 males. Additionally, F1–F3 males exhibited increased serotonin and dopamine levels and a loose arrangement of neurons in the hippocampus. We also observed a reduction in the expression of genes involved in intercellular adhesion and increased DNA methylation of the Dsc3 promoter in F1–F3 males. We concluded that tributyltin exposure led to transgenerational effects on neurodevelopment via epigenetic reprogramming in male offspring. These findings provide insights into the risks of neurodevelopmental disorders in offspring from parents exposed to tributyltin.