Abstract Antibiotics are crucial for controlling severe or invasive non-typhoidal Salmonella (NTS) infections. However, the high resistance or toxicity of traditionally first-line antibiotics calls for alternatives. The excellent membrane permeability, long half-life and safe to use in children render azithromycin a promising candidate. However, azithromycin resistance has been observed in NTS isolates recovered from humans, food, animals and the environment, with particularly high rates in Asia. Although azithromycin resistance remains low in Europe, the USA and Australia, an increasing tendency has been noted in the USA in recent years. Macrolide inactivation by phosphotransferases, methylation of 23S rRNA by methyltransferases, ribosomal protein alteration and efflux pumps are involved in azithromycin resistance in NTS isolates, among which phosphotransferase encoded by the mph (A) gene is the predominate mechanism. Current studies face limitations, such as the lack of a standardized azithromycin breakpoint for NTS isolates, insufficient integrated national surveillance and limited robust clinical evidence for treating NTS infections. Therefore, future studies addressing these issues are highly recommended.