This paper presents a practical implementation and measurement results of power-efficient chip performance optimization, utilizing low-cost indirect measurement methods to support self-X properties (self-calibration, self-healing, self-optimization, etc.) for in-field optimization of analog front-end sensory electronics with XFAB 0.35 µm complementary metal oxide semiconductor (CMOS) technology. The reconfigurable, fully differential indirect current-feedback instrumentation amplifier (CFIA) performance is intrinsically optimized by employing a single test sinusoidal signal stimulus and measuring the total harmonic distortion (THD) at the output. To enhance the optimization process, the experience replay particle swarm optimization (ERPSO) algorithm is utilized as an artificial intelligence (AI) agent, implemented at the hardware level, to optimize the performance characteristics of the CFIA. The ERPSO algorithm extends the selection producer capabilities of the classical PSO methodology by incorporating an experience replay buffer to mitigate the likelihood of being trapped in local optima. Furthermore, the CFIA circuit has been integrated with a simple power-monitoring module to assess the power consumption of the optimization solution, to achieve a power-efficient and reliable configuration. The optimized chip performance showed an approximate 34% increase in power efficiency while achieving a targeted THD value of −72 dB, utilizing a 1 Vp-p differential input signal with a frequency of 1 MHz, and consuming approximately 53 mW of power. Preliminary tests conducted on the fabricated chip, using the default configuration pattern extrapolated from post-layout simulations, revealed an unacceptable performance behavior of the CFIA. Nevertheless, the proposed in-field optimization successfully restored the circuit’s performance, resulting in a robust design that meets the performance achieved in the design phase.