Inhibition of the epidermal growth factor receptor (EGFR) reduces tumour growth and metastases and promotes axon regeneration in the central nervous system. Current EGFR inhibition strategies include the administration of reversible small-molecule tyrosine kinase inhibitors (TKIs). However, to be effective in vivo sustained delivery is required. This study explored the feasibility of encapsulating the tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) in poly(lactic-co-glycolic acid) (PLGA) microspheres using three different emulsion methods: solid-in-oil-in-water, oil-in-water and oil-in-water with co-solvent. Addition of a co-solvent increased loading and release of AG1478 and significantly (p < 0.001) decreased microsphere size. Co-solvent addition also prolonged AG1478 release from 6 months to over 9 months. Once released AG1478 remained bioactive and inhibited EGFR in immortalized rat fibroblasts and EGFR-amplified human carcinoma cells. These results demonstrate that AG1478 can be encapsulated in PLGA with sustained release and retain bioactivity; thereby providing a new platform for controlled administration of EGFR TKIs.