Spinal cord injury (SCI) results in the development of chronic pain syndromes that can persist indefinitely and cause reductions in quality of life. Treatment of chronic pain after SCI remains extremely challenging; thus, an important research goal is to determine whether early treatments can attenuate the subsequent development of pain conditions. The current study examined the hypothesis that early administration of the microglial-inhibiting drug minocycline could ameliorate the development of pain after SCI. Adult male Sprague-Dawley rats underwent SCI at the ninth thoracic spinal segment and received either vehicle or minocycline treatment for 5 days postinjury. Time course studies revealed that over 4 weeks post-SCI, microglial activation in vehicle-treated animals was progressively increased. Minocycline treatment resulted in reduction, but not prevention, of microglial activation over time. Electrophysiological experiments showed that early minocycline administration attenuated the development of chronic hyperresponsiveness of lumbar dorsal horn neurons. Similarly, behavioral assessment showed that minocycline also resulted in increased pain thresholds. These results suggest that inhibition of early neuroimmune events can have a powerful impact on the development of long-term pain phenomena following SCI and support the conclusion that modulation of microglial signaling may provide a new therapeutic strategy for patients suffering from post-SCI pain.