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Because the retina and optic nerve are an extension of the central nervous system, safety assessment of ocular compounds must include thorough examination of extraocular visual pathways, as ocular administration may result in primary toxicities in the nervous system due to its exposure to therapeutics via the retina and optic nerve, or changes that are secondary to primary ocular effects. Here we provide a practical guide to sampling extraocular visual pathway structures for commonly utilized ocular toxicology species (NHP, rabbit and rat) that is appropriate for implementation on the scale of preclinical ocular toxicity studies, highlighting examples of central nervous system toxicities following ocular administration of therapeutics. We discuss additional structures such as the ciliary ganglia, and oculomotor nerves, which may exhibit toxicities subsequent to administration of some ocular therapeutics and consider when these structures should be evaluated. 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