A camera for intraoperative imaging of tumors could improve surgical outcomes, but some imaging technologies have been difficult to translate to clinical practice. Blair et al. designed an imaging system based on the eye of the mantis shrimp. This system detected multiple near-infrared fluorescent signals simultaneously and was tested in a mouse model of human prostate cancer. In support of clinical feasibility, the authors showed that fluorescently labeled sentinel lymph nodes could be detected by the sensor in patients with breast cancer undergoing surgical resection. This bioinspired imaging sensor could offer a flexible tool for image-guided surgical removal of tumors. Cancer affects one in three people worldwide. Surgery remains the primary curative option for localized cancers, but good prognoses require complete removal of primary tumors and timely recognition of metastases. To expand surgical capabilities and enhance patient outcomes, we developed a six-channel color/near-infrared image sensor inspired by the mantis shrimp visual system that enabled near-infrared fluorescence image guidance during surgery. The mantis shrimp’s unique eye, which maximizes the number of photons contributing to and the amount of information contained in each glimpse of its surroundings, is recapitulated in our single-chip imaging system that integrates arrays of vertically stacked silicon photodetectors and pixelated spectral filters. To provide information about tumor location unavailable from a single instrument, we tuned three color channels to permit an intuitive perspective of the surgical procedure and three near-infrared channels to permit multifunctional imaging of optical probes highlighting cancerous tissue. In nude athymic mice bearing human prostate tumors, our image sensor enabled simultaneous detection of two tumor-targeted fluorophores, distinguishing diseased from healthy tissue in an estimated 92infrared structured illumination enabling the mapping of the three-dimensional topography of tumors and surgical sites to within 1.2-mm error. In the operating room, during surgical resection in 18 patients with breast cancer, our image sensor further enabled sentinel lymph node mapping using clinically approved near-infrared fluorophores. The flexibility and performance afforded by this simple and compact architecture highlights the benefits of biologically inspired sensors in image-guided surgery.