The present research assessed the efficacy of 12-week high-intensity interval training (HIIT) and blue-green algae (Spirulina) consumption on pro-inflammatory and anti-inflammatory factors (Dectin-1, IL-1β, and IL-10), along with lipid-associated signaling elements (ApoM and S1P) in obesity. We hypothesized that 12-week intervention combining HIIT and Spirulina consumption will demonstrate superior efficacy than HIIT or Spirulina alone on plasma concentrations of pro- and anti-inflammatory factors and lipid-associated signaling molecules in men with obesity. Sixty-four men with obesity (BMI ≥ 30 kg/m², 20-35 years) were randomly allocated to four treatment groups: control placebo (CP), blue-algae (BA), HIIT + placebo (HIIT+P), or HIIT + blue-algae (HIIT+BA). The treatment consisted of three weekly sessions of HIIT protocols, daily intake of 6 grams of capsulated Spirulina, or simultaneous implementation of both interventions. Plasma biomarkers (Dectin-1, IL-1β, IL-10, ApoM, and S1P), anthropometric measurements, cardiorespiratory assessments, and lipid profiles were examined at baseline and after the 12-week intervention. Statistical analyses demonstrated an elevation in plasma concentrations of IL-10 and ApoM, along with a reduction in concentrations of IL-1β in the BA, HIIT+P, and HIIT+BA groups (p < 0.05), with the most pronounced changes observed in the HIIT+BA. Also, an increase in S1P concentrations was observed in the HIIT+P and HIIT+BA groups (p = 0.03, p = 0.003, respectively). A decrease in Dectin-1 concentrations post-intervention was found only in the HIIT+BA group (p = 0.03). In conclusion, while HIIT and/or Spirulina have shown potential for targeting lipid- and inflammation-associated markers in obesity, combining these interventions demonstrates superior efficacy for certain parameters