Organisms are thriving in the deep sea at pressures up to the 1 kbar level, which imposes severe stress on the conformational dynamics and stability of their biomolecules. The impact of osmolytes and macromolecular crowders, mimicking intracellular conditions, on the effect of pressure on the conformational dynamics of a human telomeric G‐quadruplex (G4) DNA is explored in this study employing single‐molecule Förster resonance energy transfer (FRET) experiments. In neat buffer, pressurization favors the parallel/hybrid state of the G4‐DNA over the antiparallel conformation at ≈400 bar, finally leading to unfolding beyond 1000 bar. High‐pressure NMR data support these findings. The folded topological conformers have different solvent accessible surface areas and cavity volumes, leading to different volumetric properties and hence pressure stabilities. The deep‐sea osmolyte trimethylamine N‐oxide (TMAO) and macromolecular crowding agents are able to effectively rescue the G4‐DNA from unfolding in the whole pressure range encountered on Earth.