This dissertation presents a millimeter-scale CMOS 64x64 single charged particle radiation detector system for cancer radiotherapy; this work is applicable to therapies including external beam radiotherapy (EBRT), targeted radionuclide therapy (TRT), and brachytherapy. We demonstrate 1 um x 1 um diode pixels capable of measuring energy deposition into a depletion region by single charged particles. These pixels can be arrayed to provide large detection areas; we demonstrate a 512 mm x 512 mm array. Instead of sensing the voltage drop caused by radiation, the system measures pulse width, i.e., the time it takes for the voltage to return to its baseline. This obviates the need for power-hungry and large analog-to-digital converters. A prototype ASIC is fabricated in TSMC 65 nm LP CMOS process and consumes the average static power of 0.535 mW under 1.2 V power supply. The functionality of the whole system is successfully verified in a clinical 67.5 MeV proton beam setting, as well as MeV range electrons and X-ray beam produced by linear accelerator.