Ergothioneine (ERG) is a naturally occurring sulfur-containing amino acid with a unique structure. Due to its potent antioxidant properties and diverse biological functions, ERG has attracted increasing attention from researchers and is now widely used in the food, cosmetics, and pharmaceutical industries. The primary methods for obtaining ergothioneine include biological extraction, chemical synthesis, and biosynthesis. In recent years, biosynthesis has emerged as a promising production method for ergothioneine due to its environmental friendliness, low cost, and high safety. With the surging market demand for ergothioneine, there is an urgent need to develop metabolically engineered strains with high genetic stability, product concentration, and substrate utilization with low by-product formation. The discovery of native ergothioneine-producing strains and the construction of engineered strains using metabolic engineering techniques have become hot research topics. This review introduces the discovery process and applications of ergothioneine, summarizes its potential applications as an antioxidant, detoxifying agent, and neuroprotective agent in various industries, compares different production methods of ergothioneine, and focuses on the construction of engineered strains in different chassis strains. It also elucidates the research progress of various engineering strategies for the biosynthesis of ergothioneine, providing ideas and directions for its industrial production.