Chemical sensing is an important yet less developed part of Internet of things technology as it generates chemical information that is highly relevant in environment monitoring, public health, and industrial safety. To this end, nano-electronic sensory and signal transmission devices have the best technological and commercial potential for its compatibility with the existing electronic devices. The search for suitable and high-performance sensing materials and their proper incorporations into the micro-/nano-electronic platforms hold the key. For materials, nanocomposites based on graphitic carbon nanomaterials and other functional building blocks, one for signal transduction and one for molecular recognition, respectively, have achieved tremendous success in the application of chemical sensors and energy devices due to their tunable complexity and functionality. Here we summarize the design, synthesis, and device fabrication of nanocomposite materials based on single-walled carbon nanotubes and graphene, with functional building blocks including conducting polymers, metal, metal oxide, etc. Novel chemical approaches have been developed for the assembly of different building blocks, as well as their applications in chemical sensing, breath diagnostics, and energy applications. Based on the fundamental working principles of nano-electronic chemical sensing, we further demonstrate an on-chip nano-electronic-based chemical signaling technique for the investigation and improvement of sustainable energy technologies. Through the development of a novel on-chip electrical transport spectroscopy approach, we demonstrate that the electrical properties of ultrafine platinum nanowires are highly sensitive and selective to the electrochemical surface states, enabling an in situ nano-electronic signaling pathway that reveals electrochemical interface information in various energy conversion reactions. Through the new insights and newly identified nano-electronic indicators, we further demonstrate the rationally designed strategies for enhanced performance (activity, poisoning resistance, and lifetime) of energy conversion devices. Furthermore, systematic on-chip nano-electronic investigations of bioelectrochemical systems help to elucidate the complex basis of electrical conductivity of both individual microbial cells and biofilms, which will accelerate our basic understanding of earth’s microbiomes and harness the capabilities of microbial ecosystems.