Nitrogen-fixing capacity (NFC) in nodules of four Medicago truncatula lines inoculated with four strains of Sinorhizobium was assessed, during the plant life cycle, in relation to parameters identified as indices of plant growth, photosynthetic capacity, nodule integrity, and functioning. Differences in duration of the NFC period were observed among symbiotic associations and were correlated with variability on plant biomass production. Senescence appearance and vigor varied in parallel with structural, physiological, and biochemical stability of nodules. Maintenance of a longer high-NFC period was correlated to a higher stimulation of antioxidant enzymes, mainly superoxide dismutase (SOD, EC 1.15.1.1) and guaiacol peroxidase (POX, EC 1.11.1.7), and a consequent longer maintenance of membrane integrity and nodule structure within the first stages of senescence. Salinity and drought stresses interfered with nodule functioning and triggered fast and global nodule senescence, albeit a superiority of nodules having a long high-NFC period. The protective role of POX activity on salt- and drought-stressed nodules was revealed. On the other hand, SOD stimulation was independent of stress application. Another strategy allowing the maintenance of longer NFC in salt-stressed nodules could be the accumulation of starch granules in the senescence-functioning interface of nodules. This finding is currently under investigation. Interestingly, the symbioses with different behaviors of nodule senescence identified in this work would be useful bases for biochemical, genomic, and proteomic studies dissecting nodule senescence.