Spinal cord injuries (SCI) are disastrous neuropathologies causing permanent disabilities. The availability of different strains of mice is valuable for studying the pathophysiological mechanisms involved in SCI. However, strain differences have a profound effect on spontaneous functional recovery after SCI. CX3CR1+/eGFP and Aldh1l1-EGFP mice that express green fluorescent protein in microglia/monocytes and astrocytes, respectively, are particularly useful to study glial reactivity. Whereas CX3CR1+/eGFP mice have C57BL/6 background, Aldh1l1-EGFP are in Swiss Webster background. We first assessed spontaneous functional recovery in CX3CR1+/eGFP and Aldh1l1-EGFP mice over 6 weeks after lateral spinal cord hemisection. Second, we carried out a longitudinal follow-up of lesion evolution using in vivo T2-weighted magnetic resonance imaging (MRI). Finally, we performed in-depth analysis of the spinal cord tissue using ex vivo T2-weighted MRI as well as detailed histology. We demonstrate that CX3CR1+/eGFP mice have improved functional recovery and reduced anxiety after SCI compared with Aldh1l1-EGFP mice. We also found a strong correlation between in vivo MRI, ex vivo MRI, and histological analyses of the injured spinal cord in both strain of mice. All three modalities revealed no difference in lesion extension and volume between the two strains of mice. Importantly, histopathological analysis identified decreased gliosis and increased serotonergic axons in CX3CR1+/eGFP compared with Aldh1l1-EGFP mice following SCI. These results thus suggest that the strain-dependent improved functional recovery after SCI may be linked with reduced gliosis and increased serotonergic innervation.