Escherichia coli is inarguably one of the most studied microorganisms across the spectrum of microbiology. It is very widely used in recombinant protein production owing to its rapid growth, ease of genetic manipulation, and relatively high protein yields. Despite all of its advantages, its inability to efficiently secrete proteins naturally remains a drawback leading to protein aggregation as inclusion bodies in the cytoplasm and consequent low overall protein yield. Therefore, many approaches to mitigate this weakness and enhance extracellular secretion to increase protein yield have been devised. This review explores the natural and engineered secretion systems in E. coli, highlighting their potential for enhanced protein secretion for non-glycosylated proteins. Natural one-step (e.g., Type I and III Secretion Systems) and two-step systems (e.g., Sec and Tat pathways) are detailed alongside recent advancements in genetic engineering, mutagenesis, and synthetic biology approaches aimed at improving protein yield, folding, and secretion efficiency. Emerging technologies, such as the ESETEC