Bacteria frequently need to adapt to altered environmental conditions. Adaptation requires changes in gene expression, often mediated by global regulators of transcription. The nucleoid-associated protein H NS is a key global regulator in Gram-negative bacteria, and is believed to be a crucial player in bacterial chromatin organization via its DNA bridging activity. H NS activity in vivo is modulated by physico-chemical factors (osmolarity, pH, temperature) and interaction partners. Mechanistically it is unclear how functional modulation of H-NS by such factors is achieved. Here, we show that a diverse spectrum of H-NS modulators alter the ability of H-NS to bridge DNA. Changes in monovalent and divalent ion concentrations drive an abrupt switch between a bridging and non-bridging DNA binding mode. Similarly, synergistic and antagonistic co-regulators modulate the DNA bridging efficiency. Structural studies suggest a conserved mechanism: H-NS switches between a “closed” and an “open”, bridging competent, conformation driven by environmental cues and interaction partners.