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Caffeine is an adenosine A_2A receptor (<i>ADORA2A</i>) antagonist with ergogenic and anti-inflammatory effects. Previous studies have reported that the <i>ADORA2A</i> gene regulates glutamate metabolism and immune responses, with the <i>ADORA2A</i> rs5751876 TT genotype (with high sensitivity to caffeine) showing larger ergogenic effect following caffeine ingestion. We therefore hypothesized that the TT genotype would be associated with greater anti-inflammatory effects of caffeine in response to exercise, and with higher coffee intake in physically active individuals. The aim of the present study was twofold: (1) to investigate the association of the <i>ADORA2A</i> variant with the anti-inflammatory effects of caffeine in response to intense resistance exercise (RE), and (2) to analyze the association of the rs5751876 with coffee intake in physically active individuals (<i>n</i> = 134). Fifteen resistance-trained athletes participated in a randomized, double-blind, placebo-controlled cross-over study, where they consumed 6 mg/kg of caffeine or placebo one hour prior to performing an RE protocol. Blood samples were taken immediately from the arterial vein before, immediately after, and 15 min after RE for the analysis of inflammatory markers myeloperoxidase (MPO) and acetylcholinesterase (AChE). We found that the <i>ADORA2A</i> TT genotype carriers experienced lower exercise-induced inflammatory responses (<i>p</i> < 0.05 for AchE) when compared to the C allele carriers (i.e., CC/CT) one hour following the ingestion of caffeine. Furthermore, the <i>ADORA2A</i> TT genotype was positively associated with coffee intake (<i>p</i> = 0.0143; irrespective of <i>CYP1A2</i> rs762551 polymorphism). In conclusion, we found that the <i>ADORA2A</i> gene polymorphism is associated with anti-inflammatory effects of caffeine in response to resistance exercise, as well as with habitual coffee intake in physically active individuals.