Supramolecular nucleoside-based hydrogels have the potential to be utilized in drug delivery, regenerative medicine and for the construction of nanoscopic devices. Isoguanosine, its 2′-deoxyribonucleoside and the 2′-deoxy-2′-fluororibonucleoside form hydrogels in alkali metal salt solutions. Gel stability depends on the metal ions used (Li+, Na+, K+, Rb+, Cs+). All isoguanosine gels show long-term stability of several months, whereas guanosine gels collapse within minutes or hours. Rheological data confirm a 15 times higher hydrogel stability for isoguanosine compared to guanosine. Isoguanosine gel stability covers a broad pH range (pH 3–10), and the stability at physiological Na+ ion concentration is striking. SEM images reveal that isoguanosine self-assembles into helical stacked fibers that are interconnected whereas guanosine forms discrete ribbons. Moreover, isoguanosine gels display excellent loading and release ability for small molecules.