Bioelectronics is an interdisciplinary field of research that aims to establish a synergy between electronics and biology. Contributing to a deeper understanding of bioelectronic processes and the built bioelectronic systems, a variety of new phenomena, mechanisms and concepts have been derived in the field of biology, medicine, energy, artificial intelligence science, etc. Organic semiconductors can promote the applications of bioelectronics in improving original performance and creating new features for organisms due to their excellent photoelectric and electrical properties. Recently, water-soluble conjugated polymers (WSCPs) have been employed as a class of ideal interface materials to regulate bioelectronic processes between biological systems and electronic systems, relying on their satisfying ionic conductivity, water-solubility, good biocompatibility and the additional mechanical and electrical properties. In this review, we summarize the prominent contributions of WSCPs in the aspect of the regulation of bioelectronic processes and highlight the latest advances in WSCPs for bioelectronic applications, involving biosynthetic systems, photosynthetic systems, biophotovoltaic systems, and bioelectronic devices. The challenges and outlooks of WSCPs in designing high-performance bioelectronic systems are also discussed.