2,5-Furandicarboxylic acid (FDCA), mainly synthesized by the selective oxidation of 5-hydroxymethylfurfural (HMF), is a biobased monomer for high-performance polymers. In this work, we have a comprehensive investigation on the rapid and highly selective oxidation process of HMF to FDCA in acetic acid (HAc) with Co/Mn/Br catalyst and air as the oxidant. It was found that both aldehyde and hydroxymethyl functional groups of HMF could be first oxidized in the sequential oxidation of HMF to FDCA, but 2,5-diformylfuran (DFF) was the main oxidation intermediate. Apart from the side reaction of HMF overoxidation to COx (CO and CO2) and HMF condensation to polymers, a small part of HMF will be further oxidized to maleic acid (MA) and fumaric acid (FA) via the ring-opening reactions under severe conditions because of the instability of furan ring. To reduce the side reactions and maximize the FDCA yield, the effects of temperature, pressure, substrate solvent ratio, catalyst composition and concentration, and water concentration on the main reactions and side reactions of the HMF oxidation were systematically evaluated. Under the optimum conditions, the selectivity of FDCA reached 92% with the total conversion of HMF in less than 20 min at a high mass ratio of substrate and solvent (1/9), and the purity of FDCA exceeded 99.8%. The experimental results provide a great reference and inspiration for the optimization of the HMF oxidation process and the large-scale production of FDCA.