The　increasing　demand　and　use　of　antibiotics　due　to　epidemic　outbreaks　under　climate　change　leads　to　more　antibacterial　substances　entering　the　environment.　The　residual　drugs,　commonly　found　as　mixtures,　can　specially　target　bacteria,　posing　a　threat　to　the　ecosystem　and　human　health.　Therefore,　it　is　necessary　to　assess　the　risk　of　antibiotic　mixtures　using　bacteria　as　the　model　organisms.　In　this　study,　selecting　sulfonamides,　sulfonamides　potentiators,　and　tetracyclines　as　the　representative　antibiotics,　the　individual　and　combined　toxicity　of　these　agents　were　tested　against　Gram-positive　(Bacillus　subtilis)　and　Gram-negative　bacteria　(Aliivibrio　fischeri　and　Escherichia　coli).　The　quantitative　structure–activity　relationship　models　were　constructed　by　setting　Ebind　(lowest　interaction　energy　between　antibiotic　and　target　protein)　and　Kow　(octanol–water　partition　coefficient)　as　the　structural　descriptors,　which　provide　reliable　and　robust　tools　for　predicting　the　toxicity　of　single　agents　and　binary　mixtures.　Furthermore,　the　hormetic　effects,　characterized　by　low-dose　stimulation　and　high-dose　inhibition,　were　observed　in　Gram-negative　bacteria,　and　the　dose-responses　in　Gram-positive　bacteria　all　exhibited　S-shaped.　Within　the　hormetic　phenomena　of　antibiotic　mixtures,　the　pattern　of　joint　toxic　action　and　component　contribution　generally　changed　with　the　transition　from　stimulatory　to　inhibitory　actions.　These　results　not　only　demonstrate　the　influence　of　bacterial　species　and　test　endpoints　on　the　toxicity　of　antibiotics,　but　also　clarify　the　pivotal　role　of　hormesis　in　the　joint　effects　of　antibiotics.　This　study　provides　a　data-driven　methodology　for　evaluating　the　combined　toxicity　of　mixtures,　which　will　promote　the　development　of　the　risk　assessment　of　antibiotics　and　other　environmental　pollutants.　©　2025　The　Author(s)