A 16-channel closed-loop neuromodulation system-on-chip (SoC) for human epileptic seizure control is proposed and designed. In the proposed SoC, a 16-channel neural-signal acquisition unit (NSAU), a biosignal processor (BSP), a 16-channel high-voltage-tolerant stimulator (HVTS), and wireless power and bidirectional data telemetry are designed. In the NSAU, the input protection circuit is used to prevent MOSFET from overstressing by the high-voltage stimulations. Hence, NSAUs can share electrodes with stimulators. The auto-reset chopper-stabilized capacitive-coupled instrumentation amplifiers (AR-CSCCIAs) are designed with the chopper-stabilized technique with a new offset reduction loop. The measured input-referred noise is 2.09 <inline-formula> <tex-math notation="LaTeX">\mu \textrm {V}_{\mathrm {rms}} </tex-math></inline-formula> and the noise-efficiency factor (NEF) is 3.78. The entropy-and-spectrum seizure detection algorithm is implemented in the BSP with 0.76-s seizure detection latency and 97.8% detection accuracy. When the seizure onset is detected by the BSP, the HVTS with adaptive supply control delivers 0.5-3-mA biphasic current stimulation to suppress the seizure onset. The proposed SoC is powered wirelessly, and the bidirectional data telemetry is realized through the same pair of coils in 13.56 MHz. The downlink data rate is 211 Kb/s with the binary phase-shift keying (BPSK) modulation and a new BPSK demodulator. The uplink data rate is 106 Kb/s with the load-shift keying (LSK) modulation. The proposed SoC is fabricated in a 0.18-<inline-formula> <tex-math notation="LaTeX">\mu \text{m} </tex-math></inline-formula> CMOS technology and occupies 25 mm 2 . Electrical tests have been performed to characterize the SoC performance. In vivo animal experiments using mini-pigs have been performed to successfully verify the closed-loop neuromodulation functions on epileptic seizure suppression.