The work aims to realize the compressive stress and anti-fatigue manufacturing of titanium alloy, propose the compound processing of longitudinal-torsional ultrasonic vibration and milling (LTUM), study the Ti-6Al-4V through experiment and explore the influence laws of process parameters on residual stress. The differences of cutting force, cutting temperature and residual stress between ultrasonic and traditional milling were analyzed through the experiment. The effects of processing parameters, cooling-lubrication conditions and tool wear on residual stress were studied by orthogonal and single factor experiments in consideration of the interaction of factors. Compared with traditional milling, LTUM reduced cutting force by about 16.3% and cutting temperature by about 25.6%, and increased the residual compressive stress (RCS) by about 31.3%. Within the range of selected parameters, radial depth had a greater influence on the RCS (contribution rate of 34.1%), while ultrasonic amplitude had a smaller influence (contribution rate of 6.5%). RCS decreased with the increase of milling speed, feed per tooth and radial depth, and increased with the increase of ultrasonic amplitude. When emulsified fluid was used as cutting fluid, RCS increased, while the RCS of dry cutting was equivalent to that of water and oil cutting fluids. RCS decreased with the increase of tool wear. LTUM effectively reduces the cutting force and temperature and increases the RCS. Appropriate process parameters and lubrication-cooling conditions should be chosen to further increase the RCS, and LTUM can be used as a reliable compressive stress manufacturing technology.