The development of systems capable of responding to environmental changes, such as humidity, requires the design and assembly of highly sensitive and efficiently transducing elements. Such a challenge can be mastered only by disentangling the role played by each component of the responsive system, thus ultimately achieving high performance by optimizing the synergistic contribution of all functional elements. Here, we designed and synthesized a novel [1]benzothieno[3,2-b][1]benzothiophene derivative equipped with hydrophilic oligoethylene glycol lateral chains (OEG-BTBT) that can electrically transduce subtle changes in ambient humidity with high current ratios (>104) at low voltages (2 V), reaching state-of-the-art performance. Multiscale structural, spectroscopical, and electrical characterizations were employed to elucidate the role of each device constituent, viz., the active material's BTBT core and OEG side chains, and the device interfaces. While the BTBT molecular core promotes the self-assembly of (semi)conducting crystalline films, its OEG side chains are prone to adsorb ambient moisture. These chains act as hotspots for hydrogen bonding with atmospheric water molecules that locally dissociate when a bias voltage is applied, resulting in a mixed electronic/protonic long-range conduction throughout the film. Due to the OEG-BTBT molecules' orientation with respect to the surface and structural defects within the film, water molecules can access the humidity-sensitive sites of the SiO2 substrate surface, whose hydrophilicity can be tuned for an improved device response. The synergistic chemical engineering of materials and interfaces is thus key for designing highly sensitive humidity-responsive electrical devices whose mechanism relies on the interplay of electron and proton transport.