Archaea are major, ubiquitous constituents of complex microbiomes, yet we know little about their responses to antimicrobial challenge or their ability to develop resistance to antibiotic agents. Archaea inhabit many ecological niches where they may be exposed to chronic, sub-lethal antimicrobials including antibiotics, biocides and other non-antimicrobial drivers of acquired resistance, yet are largely overlooked in AMR or One Health research. Focusing on a unique and previously unstudied terrestrial hypersaline microbiota, Kilroot salt mine in Carrickfergus, NI, an extensive series of Triassic halite deposits formed 250-220 million years ago. The extremely halophilic archaea (haloarchaea) isolated from this environment represent accessible, aerobic and extremophilic model organisms for examining fundamental processes such as antimicrobial resistance and tolerance, persistence, and responses to sub-lethal antimicrobial challenge. We demonstrate that archaea, isolated from brine inclusions within ancient halite structures exhibit persister cell formation in response to starvation, and antimicrobials, which may be self-induced by QS-like molecules. In addition, the first identification and characterisation of two functional antibiotic MATE efflux pumps in Halorubrum amylolyticum, which alter the susceptibility of these archaea to broad range of antibiotics and biocides and which are susceptible selective efflux pump inhibitors, is reported. Molecular modelling reveals binding sites for both antibiotics and EPIs in these pumps. Finally, the evolution of antibiotic resistance in archaea is demonstrated for the first time, through repeated exposure to sub-lethal ciprofloxacin concentrations, via mutation of a single nucleotide in a region of archaeal gyrase A analogous to the Quinolone Resistance Determining Region in bacterial DNA gyrases.