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The article presents for the first time a pill-based ingestible electronics with CMOS integrated multiplexed fluorescence bio-molecular sensor arrays, bi-directional wireless communication and packaged optics in a FDA-approved capsule for in-vivo bio-molecular sensing. The silicon chip integrates both the sensor array, and the ultra-low-power (ULP) wireless system that allows offloading sensor computing to an external base station that can reconfigure the sensor measurement time, and its dynamic range, allowing optimized high sensitivity measurement under low power consumption. The integrated receiver achieves −59 dBm receiver sensitivity dissipating 121 µW of power. The integrated transmitter operates in a dual mode FSK/OOK delivering −15 dBm of power. The 15-pixel fluorescence sensor array follows an electronic-optic co-design methodology and integrates the nano-optical filters with integrated sub-wavelength metal layers that achieves high extinction ratio (39 dB), thereby eliminating the need for bulky external optical filters. The chip integrates photo-detection circuitry and on-chip 10-bit digitation, and achieves measured sensitivity of 1.6 attomoles of fluorescence labels on surface, and between 100 pM to 1 nM of target DNA detection limit per pixel. The complete package includes a CMOS fluorescent sensor chip with integrated filter, a prototyped UV LED and optical waveguide, functionalized bioslip, off-chip power management and Tx/Rx antenna that fits in a standard FDA approved capsule size 000.