For discriminating the signals of multi-targets, multiplexed photoelectrochemical (PEC) detection is generally accomplished by modulating the light source or voltage, which prospect is usually limited by expensive instrumentation, tedious operational steps, and time-consuming material screening. To realize multiplexed determination on single photoelectric interface using the routine technique, a non-instrument-assisted strategy for signal discrimination needs to be explored. Herein, we propose an exonuclease III-mediated multiple PEC signals resolution strategy and construct a self-cleaning recyclable multiplexed PEC sensor using a porphyrin-bipyridine-based covalent organic framework (Por-Bpy COF) photocathode. Specifically, following the dual-target recognition event, exonuclease III cleaves the DNA strand attached to the magnetic bead so that the two signal labels can be separated. Once the signal label binds to the DNA on the electrode surface (E-DNA), exonuclease III turns to excise the DNA strand of the signal label and consequently the E-DNA can repeatedly bind different signal labels. As a result, distinguishable photocurrent signals of different targets can be generated on a single photoelectric interface. The feasibility of this multiplexed sensor is verified by detecting two coexisting mycotoxins aflatoxin B1 and zearalenone. On account of eliminating the instrumentation constraints and simplifying the experimental procedures, the proposed sensing strategy may provide a brand-new idea for the exploration of portable multiplexed PEC sensing devices.