The strength and ductility trade-off is a long-standing issue of single face-center-cubic (FCC) high entropy alloys (HEAs). In the present work, the in-situ formation of heterogeneous grain structure coupled with the introduction of Y2O3 nanoparticles in FCC structure Ni26Co26Fe25Cu17Ti6 HEA is proposed as a strategy to enhance the strength and ductility synergy. The oxide dispersion strengthened (ODS) Ni26Co26Fe25Cu17Ti6 HEAs were fabricated by mechanical alloying (MA) and spark plasma sintering (SPS) methods and the influences of different Y2O3 additions on the evolutions of oxide precipitates, heterogeneous microstructure and mechanical properties of ODS-HEAs were systematically investigated. The results show that the introduction of Y2O3 facilitates the new precipitation of finer and semi-coherent Y2Ti2O7 oxide nanoparticles, in addition to the protogenous TiO in the Ti-containing HEA matrix. All the studied ODS-HEAs display the bimodal grain microstructure, in which numerous oxide dispersoids are distributed exclusively in the fine-grained (FG) region. With the increase of Y2O3 addition, the average grain size of FG region first decreases and then increases in ODS-HEA, while the proportion of FG region shows the opposite trend. When the content of Y2O3 is 1.05 wt%, the yield strength, ultimate tensile strength and elongation to fracture of ODS-HEA at room temperature are 21%, 27% and 157%, respectively, higher than those of Ni26Co26Fe25Cu17Ti6 base alloy. The simultaneous enhancement of strength and ductility in ODS-HEA by introducing a proper amount of Y2O3 is mainly attributed to the additional precipitation strengthening contribution of generated Y2Ti2O7 oxide nanoparticles having semi-coherent interfaces with the FCC matrix.