This study investigated the influence of nano-powder type on the surface integrity of Ti-6Al-4V titanium alloy during powder-mixed electrical discharge machining (PMEDM). Three nano-powder conditions, namely hydroxyapatite (HA), yttria-stabilized zirconia (YSZ), and a mixed powder (50 wt.% HA + 50 wt.% YSZ), were dispersed in deionized water at a constant concentration of 1 g/L. The powder concentration was selected based on preliminary experiments, while continuous ultrasonic dispersion and mechanical stirring were employed to ensure homogeneous particle distribution throughout the machining process. A three-factor, three-level full factorial design comprising 27 experimental runs was conducted to evaluate the effects of peak current (18–30 A), pulse-on time (100–200 µs), and powder type on two key surface integrity responses: surface roughness (Ra) and recast layer thickness (RLT). The experimental results showed that both peak current and pulse-on time significantly affected the surface characteristics. Increasing the discharge energy generally increased the amount of material melted and re-solidified, resulting in higher surface roughness and thicker recast layers. The powder type also played a crucial role in determining machining performance, demonstrating its influence on discharge stability and surface quality. Grey Relational Analysis (GRA) was employed for multi-response optimization by simultaneously considering surface roughness and recast layer thickness. Among the 27 experimental runs, Experiment 14 achieved the highest Grey Relational Grade (GRG = 0.855), indicating the best overall machining performance by providing the most favorable combination of low surface roughness and minimum recast layer thickness. Overall, the findings confirm that nano-powder mixed EDM is an effective approach for improving the surface integrity of Ti-6Al-4V alloy. The study further demonstrates that appropriate selection of machining parameters and ceramic nano-powders can significantly enhance the surface characteristics of titanium alloys, highlighting the potential of PMEDM for advanced biomedical implant applications.