Triggering the release of small molecules in response to unique biomarkers is important for applications in drug delivery and biodetection. Due to typically low quantities of biomarker, amplifying release is necessary to gain appreciable responses. Nucleic acids have been used for both their biomarker recognition properties and as stimuli, notably in amplified small molecule release via nucleic acid‐templated catalysis (NATC). The multiple components and reversibility of NATC, however, make it difficult to apply in vivo . Here, we report the first use the hybridization chain reaction (HCR) for the amplified, conditional release of small molecules from standalone nanodevices. We first couple HCR with a DNA‐templated reaction resulting in the amplified, immolative release of small molecules. Moreover, we integrate the HCR components into single nanodevices as DNA tracks and spherical nucleic acids, spatially isolating reactive groups until triggering. Overall, this work translates the amplification of HCR into small molecule release without the use of multiple components, and will aid its application to biosensing, imaging and drug delivery.