Spent coffee grounds (SCG), the residue after brewing coffee beverage, is a promising biodiesel feedstock due to its high oil contents (15‒20%). However, SCG should be pretreated to reduce the high free fatty acid content, which hampers transesterification reaction. To overcome this, we explored a direct transesterification reaction of SCG using ultrasound irradiation and identified the optimal sonication parameters. A high fatty acid methyl ester (FAME) content, up to 97.2%, could be achieved with ultrasound amplitude of 99.2 <i>μ</i>m, irradiation time of 10 min, and methanol to oil ratio of 7:1 in the presence of potassium hydroxide concentration of 1.25 wt.%. In addition, we demonstrated that ultrasound irradiation is an efficient method to produce biodiesel from untreated SCG in a short time with less energy than the conventional mechanical stirring method. The physical and chemical properties of the SCG biodiesel met the requirements for an alternative fuel to the current commercial biodiesel.