As an emerging therapeutic gas, hydrogen (H2) is gifted with excellent biosafety, high tissue permeability, and radical-trapping capacity and is extensively considered as a highly promising antioxidant in clinics. However, a facile and effective strategy of H2 production for major inflammatory disease treatments is still lacking. In this study, by a facile wet-chemical exfoliation synthesis, a hydrogen-terminated silicon nanosheet (H-silicene) has been synthesized, which can favorably react with environmental water to generate H2 rapidly and continuously without any external energy input. Furthermore, theoretical calculations were employed to reveal the mechanism of enhanced H2 generation efficacy of H-silicene nanosheets. The as-synthesized H-silicene has been explored as a flexible hydrogen gas generator for efficient antioxidative stress application for the first time, which highlights a promising prospect of this two-dimensional H-silicene nanomaterial for acute inflammatory treatments by on-demand H2 production-enabled reactive oxygen species scavenging. This study provides a novel and efficient modality for nanomaterial-mediated H2 therapy.