Snakehead, Channa striata, has a long history of invasion and associated negative impacts on the biodiversity of native aquatic organisms in the Mekong Delta. However, internal white spot disease caused by Aeromonas schubertii has a massive effect on the production of snakehead fish but also can spread to wild populations and to consumers. The aim of the study was to investigate the prevalence of multi‐antibiotic resistance (MAR) of A. schubertii isolated from snakehead fish cultured in several Mekong Delta fish farms, as well as its potential to spread throughout the infection season. Based on morphological and biochemical tests, as well as phylogenetic analysis of three housekeeping genes (16S rRNA, gyrB, and rpoD), isolates recovered from white nodules were strongly identified as A. schubertii. The antibiotic susceptibility testing revealed that all of the isolates (n = 25) were phenotypically multidrug‐resistant, with resistance to erythromycin (84%), rifampicin (84%), flumequine (88%), amoxicillin (96%), ciprofloxacin (92%), and florfenicol (92%). The multiple antibiotic resistance indices ranged from 0.33 to 0.92, with A. schubertii isolate As28 being resistant against 11 out of the 12 tested antibiotics. In particular, 15 MAR phenotypes (MARPs) were found in 25 isolates with 8 isolates (32%) commonly displaying MAR phenotypes against patterns of Ery–Rif–Flq–Aml–Cip–Flo, and four isolates (16%) expressing patterns of Ery–Rif–Nov–Flq–Aml–Cip–Flo. A hierarchical clustering analysis of their antibiotic‐resistant bacteria may indicate cross‐invasion between ponds/fish farms and its ability to survive in aquatic environments for long periods (at least 3 months). Our results suggest that the diversity of MARPs bacteria in snakehead represents a potential hazard to modifying the composition of native aquatic organisms, especially to consumers. To successfully manage C. striata in the future, several eco‐friendly techniques should be used to restrict the spread of A. schubertii inside the invaded habitat of the Mekong Delta river.