The long-term effects of Chlorella doses on the inflammatory status and quality of life (QoL) of individuals with type-2 diabetes (T2D), and prediabetes (pre-T2D), and of nondiabetic controls were investigated. Chlorella was administered for 12 months; 1.6 g/day for the first six months and 3 g/day for the following six months. The inflammatory profile was studied by quantification of cytokines, adipokines and incretins. QoL was evaluated using the Short Form-36 health survey questionnaire (SF-36). Evaluations were performed at baseline, 6 (T6) and 12 (T12) months after initiating Chlorella intake. At baseline, QoL was more deeply impacted in T2D, a similar proinflammatory profile was observed in T2D and pre-T2D. In both, at T6 and T12, Chlorella modulated the altered levels of adipocytokines and incretins towards healthy values, and significantly improved QoL. Moderate correlations between the modulation by the alga and enhancement in QoL were observed only in the T2D group. In the nondiabetic control group, Chlorella improved QoL vitality and mental health scores. No differences were found between the two doses. Our results illustrate Chlorella adaptogen activity on inflammatory pathways and suggest its promising use as a complementary alternative in treating diseases related to insulin resistance in a wide range of chronic low-grade systemic inflammation-related diseases. Moreover, Chlorella increased QoL in all groups, the ultimate goal of all healthy interventions. Altogether, our findings suggest that one core mechanism involved in the homeostatic response produced by Chlorella is related to its rich content of carotenoids, operating mainly through inhibition of the NF-κB signalling pathway.