Habitat disturbance from development, resource extraction, off-road vehicle use, and energy development ranks highly among threats to desert systems worldwide. In the Mojave Desert, United States, these disturbances have promoted the establishment of nonnative plants, so that native grasses and forbs are now intermixed with, or have been replaced by invasive, nonnative Mediterranean grasses. This shift in plant composition has altered food availability for Mojave Desert tortoises (Gopherus agassizii), a federally listed species. We hypothesized that this change in forage would negatively influence the physiological ecology, immune competence, and health of neonatal and yearling tortoises. To test this, we monitored the effects of diet on growth, body condition, immunological responses (measured by gene transcription), and survival for 100 captive Mojave tortoises. Tortoises were assigned to one of five diets: native forbs, native grass, invasive grass, and native forbs combined with either the native or invasive grass. Tortoises eating native forbs had better body condition and immune functions, grew more, and had higher survival rates (>95%) than tortoises consuming any other diet. At the end of the experiment, 32% of individuals fed only native grass and 37% fed only invasive grass were found dead or removed from the experiment due to poor body conditions. In contrast, all tortoises fed either the native forb or combined native forb and native grass diets survived and were in good condition. Health and body condition quickly declined for tortoises fed only the native grass (Festuca octoflora) or invasive grass (Bromus rubens) with notable loss of fat and muscle mass and increased muscular atrophy. Bromus rubens seeds were found embedded in the oral mucosa and tongue in most individuals eating that diet, which led to mucosal inflammation. Genes indicative of physiological, immune, and metabolic functions were transcribed at lower levels for individuals fed B. rubens, indicating potential greater susceptibility to disease or other health-related problems. This study highlights the negative indirect effects of invasive grasses, such as red brome, in desert ecosystems, and provides definitive evidence of a larger negative consequence to health, survival, and ultimately population recruitment for Mojave Desert tortoises than previously understood.