Modern medicine is increasingly interested in advanced sensors to detect and analyze biochemical indicators. Ion sensors based on potentiometric methods are a promising platform for monitoring physiological ions in biological subjects. Current semi-implantable devices are mainly based on single-parameter detection. Miniaturized semi-implantable electrodes for multiparameter sensing have more restrictions on the electrode size due to biocompatibility considerations, but reducing the electrode surface area could potentially limit electrode sensitivity. This study developed a semi-implantable device system comprising a multiplexed microfilament electrode cluster (MMEC) and a printed circuit board for real-time monitoring of intra-tissue K+, Ca2+, and Na+ concentrations. The electrode surface area was less important for the potentiometric sensing mechanism, suggesting the feasibility of using a tiny fiber-like electrode for potentiometric sensing. The MMEC device exhibited a broad linear response (K+: 2–32 mmol/L; Ca2+: 0.5–4 mmol/L; Na+: 10–160 mmol/L), high sensitivity (about 20–45 mV/decade), temporal stability (>2 weeks), and good selectivity (>80%) for the above ions. In vitro detection and in vivo subcutaneous and brain experiment results showed that the MMEC system exhibits good multi-ion monitoring performance in several complex environments. This work provides a platform for the continuous real-time monitoring of ion fluctuations in different situations and has implications for developing smart sensors to monitor human health.Graphic abstract: