Acute mesenteric ischemia (AMI) results from insufficient blood flow to the intestines, leading to tissue necrosis with high morbidity and mortality. Diagnosis is often delayed because of nonspecific symptoms that mimic common gastrointestinal conditions. Current diagnostic methods, such as computed tomography and mesenteric angiography, are complex, costly, and invasive, highlighting the need for a rapid, accessible, and minimally invasive alternative. Here, we present FIREFLI (finding ischemia via reflectance of light), a bioinspired, ingestible capsule designed for luminance-based diagnosis of AMI. Upon ingestion, the device activates in the small intestine’s pH environment, emitting pulses from three radially spaced white light-emitting diodes and measuring reflected light across 10 wavelengths. FIREFLI then computes a tissue luminance biomarker, which outperforms color-change biomarkers because of superior intrasubject consistency. The diagnosis is processed onboard and wirelessly transmitted to an external mobile device. In vivo studies in swine (n = 9) demonstrated a diagnostic accuracy of 90%, with a sensitivity of 98% and specificity of 85%. By providing a noninvasive, real-time diagnostic solution, FIREFLI has the potential to facilitate earlier detection and treatment of AMI, ultimately improving patient outcomes.