5-Hydroxymethylfiirfural (HMF), an organic platform chemical, used as a precursor of various industrial chemicals, was synthesized from waste coffee grounds (WCG), glucose, and fructose, using Al(NO3)(3) and H2SO4 as catalysts, in a highly aqueous binary solvent system consisting of water and dimethyl sulfoxide (DMSO) and a conventional microwave as the heating system. The effect of tuning the water/DMSO ratio was first studied. Results showed that the highest HMF yield can be obtained using 6:4, 5:5, and 7:3 water/DMSO ratios for WCG, glucose, and fructose, respectively. A response surface methodology was also employed to determine the interactions among catalyst loading, reaction time, and microwave power and their effects HMF yield. Yields of up to 13.65% (WCG), 28.50% (glucose), and 60.8% (fructose) were observed. This study demonstrates the use of WCG as an HMF precursor and the tuning of several experimental factors to increase the HMF yield from simple sugars and WCG.