Gastric mucosal injury, the most common adverse effect of non-steroidal anti-inflammatory drugs, severely threatens human health. Existing therapeutic drugs face many challenges, including side effects, drug interactions, and high injury recurrence. Evodiamine alkaloids isolated from the traditional Chinese medicine plant Evodia rutaecarpa exhibit superior therapeutic characteristics for treating gastric injury. This study was aimed at developing a formulation of rhEGF-conjugated evodiamine bovine serum albumin nanoparticles (rhEGF/[email protected] NPs) to promote the repair of indomethacin-associated gastric mucosal injury in male SD rats. RhEGF/[email protected] NPs were characterized in detail. The therapeutic efficacy and biodistribution of rhEGF/[email protected] NPs were evaluated using an indomethacin-associated gastric mucosal injury model in vivo and in vitro. Cytotoxicity assays demonstrated rhEGF/[email protected] NPs had good biocompatibility. RhEGF/[email protected] NPs increased cell proliferation and showed enhanced uptake by GES-1 cells through clathrin-mediated endocytosis. In vivo experiments indicated that rhEGF/[email protected] NPs promoted mucosal repair by decreasing serum IL-6 and TNF-α levels, decreasing COX-2 levels and elevating NO levels in gastric tissue. Biodistribution in gastric tissue experiments showed that rhEGF/[email protected] NPs were deposited in lesions at higher levels than unmodified [email protected] NPs. Thus, rhEGF/[email protected] NPs alleviated IND-associated gastric mucosal injury by regulating the inflammatory response and increasing drug concentrations in the lesion areas. This study demonstrates a promising strategy for ameliorating IND-associated gastric mucosal injury.