Objective: To determine the effect of marathon running on serum levels of inflammatory, high energy, and cartilage matrix biomarkers and to ascertain whether these biomarkers levels correlate.Design: Blood samples from 17 Caucasian male recreational athletes at the Barcelona Marathon 2017 were collected at the baseline, immediately and 48 h post-race. Serum C reactive protein (CRP), creatin kinase (CK), and lactate dehydrogenase (LDH) were determined using an AU-5800 chemistry analyser. Serum levels of hyaluronan (HA), cartilage oligomeric matrix protein (COMP), aggrecan chondroitin sulphate 846 (CS846), glycoprotein YKL-40, human procollagen II N-terminal propeptide (PIINP), human type IIA collagen N-propeptide (PIIANP), and collagen type II cleavage (C2C) were measured by sandwich enzyme-linked immune-sorbent assay (ELISA).Results: Medians CK and sLDH levels increased (three-fold, two-fold) post-race [429 (332) U/L, 323 (69) U/L] (p < 0.0001; p < 0.0001) and (six-fold, 1.2-fold) 48 h post-race [658 (1,073) U/L, 218 (45) U/L] (p < 0.0001; p < 0.0001). Medians CRP increased (ten-fold) after 48 h post-race [6.8 (4.1) mg/L] (p < 0.0001). Mean sHA levels increased (four-fold) post-race (89.54 ± 53.14 ng/ml) (p < 0.0001). Means PIINP (9.05 ± 2.15 ng/ml) levels increased post-race (10.82 ± 3.44 ng/ml) (p = 0.053) and 48 h post-race (11.00 ± 2.96 ng/ml) (p = 0.001). Mean sC2C levels (220.83 ± 39.50 ng/ml) decreased post-race (188.67 ± 38.52 ng/ml) (p = 0.002). In contrast, means COMP, sCS846, sPIIANP, and median sYKL-40 were relatively stable. We found a positive association between sCK levels with sLDH pre-race (r = 0.758, p < 0.0001), post-race (r = 0.623, p = 0.008) and 48-h post-race (r = 0.842, p < 0.0001); sHA with sCRP post-race vs. 48 h post-race (r = 0.563, p = 0.019) and sPIINP with sCK pre-race vs. 48-h post-race (r = 0.499, p = 0.044) and with sLDH 48-h pre-race vs. post-race (r = 0.610, p = 0.009) and a negative correlation of sPIIANP with sCRP 48-h post-race (r = −0.570, p = 0.017).Conclusion: Marathon running is an exercise with high-energy demands (sCK and sLDH increase) that provokes a high and durable general inflammatory reaction (sCRP increase) and an immediately post-marathon mechanism to protect inflammation and cartilage (sHA increase). Accompanied by an increase in type II collagen cartilage fibrils synthesis (sPIINP increase) and a decrease in its catabolism (sC2C decrease), without changes in non-collagenous cartilage metabolism (sCOMP, sC846, and sYKL-40). Metabolic changes on sPIINP and sHA synthesis may be related to energy consumption (sCK, sLDH) and the inflammatory reaction (sCRP) produced.