This study presents a real-time monitoring technique for radioactive substances that meets safety management needs. We studied the accumulation characteristics of radiation response signals of monolithic active pixel sensors (MAPSs) based on their response and discrimination ability to gamma (γ) photon or neutron radiation. The radiation status of the radioactive substances was determined by monitoring the accumulation data of radiation responses. As per the results, Am-Be and 252Cf radiation response signals are primarily concentrated in the range of 0–70 pixels. Response signals of 60Co and 137Cs γ-ray were concentrated in two regions; there was a peak in the region with a pixel value of less than 50, and a plateau in the region with a pixel value of more than 75. Therefore, the results are able to discriminate between spectra. Furthermore, we designed a radioactivity monitoring system that is able to examine multiple radioactive materials. Its working principle is that a change in the accumulation of radioactivity monitoring data indicates a radiation change during the last accumulation cycle. This study provides vital technical support for the long-term supervision of radioactive substances.