Objective. We propose a single-ended readout, multi-resolution detector design that can achieve high spatial, depth-of-interaction (DOI), and time-of-flight (TOF) resolutions, as well as high sensitivity for human brain-dedicated positron emission tomography (PET) scanners. Approach. The detector comprised two layers of LYSO crystal arrays and a lightguide in between. The top (gamma ray entrance) layer consisted of a 16 × 16 array of 1.53 × 1.53 × 6 mm3 LYSO crystals for providing high spatial resolution. The bottom layer consisted of an 8 × 8 array of 3.0 × 3.0 × 15 mm3 LYSO crystals that were one-to-one coupled to an 8 × 8 multipixel photon counter (MPPC) array for providing high TOF resolution. The 2 mm thick lightguide introduces inter-crystal light sharing that causes variations of the light distribution patterns for high DOI resolution. The detector was read out by a PETsys TOFPET2 application-specific integrated circuit. Main result. The top and bottom layers were distinguished by a convolutional neural network with 97% accuracy. All crystals in the top and bottom layers were resolved. The inter-crystal scatter (ICS) events in the bottom layer were identified, and the measured average DOI resolution of the bottom layer was 4.1 mm. The coincidence time resolution (CTR) for the top–top, top-bottom, and bottom–bottom coincidences was 476 ps, 405 ps, and 298 ps, respectively. When ICS events were excluded from the bottom layer, the CTR of the bottom–bottom coincidence was 277 ps. Significance. The top layer of the proposed two-layer detector achieved a high spatial resolution and the bottom layer achieved a high TOF resolution. Together with its high DOI resolution and detection efficiency, the proposed detector is well suited for next-generation high-performance brain-dedicated PET scanners.