Antimicrobial resistance is becoming a critical issue due to the widespread and indiscriminate use of antibiotics and antifungals to treat common infections, leading to a growing shortage of effective drugs. Moreover, the increase in antimicrobial resistance is enhancing the pathogenicity and virulence of various pathogens. Microorganisms are key sources of chemically diverse specialized metabolites, which are produced in the final stages of their growth cycle. These metabolites hold significant value in chemical, pharmaceutical, and agrochemical industries. One of the major challenges researchers face in this field is the frequent isolation of already-known substances when classical protocols are used. To address this, several innovative strategies have been developed. The co-culture approach is a powerful tool for activating silent biosynthetic gene clusters, as it simulates natural microbial environments by creating artificial microbial communities. This method has shown promising results, with new compounds being isolated and the yields of target substances being improved. In this context, this review provides examples of antimicrobial compounds obtained from co-cultures of endophytic fungi, conducted in both liquid and solid media. Additionally, the review discusses the advantages and challenges of the co-culture technique. Significance and Impact of the Study: Microbial co-culture is a valuable strategy for discovering new natural products with antimicrobial activity, as well as for scaling up the production of target substances. This review aims to summarize important examples of endophyte co-cultures and highlights the potential of endophytic fungi co-culture for pharmacological applications.