Medium-entropy alloys (MEAs) are prospective structural materials for emerging advanced nuclear systems because of their outstanding mechanical properties and irradiation resistance. In this study, the microstructure and mechanical properties of three new single-phase body-centered cubic (BCC) structured MEAs (Zr40Nb35Ti25, Zr50Nb35Ti15, and Zr60Nb35Ti5) before and after irradiation were investigated. It is shown that the yield strength and elongation after fracture at room temperature are greater than 900 MPa and 10%, respectively. Three MEAs were irradiated with 3 MeV Fe11+ ions to 8 × 1015 and 2.5 × 1016 ions/cm2 at temperatures of 300 and 500 °C, to investigate the irradiation-induced hardening and microstructure changes. Compared with most conventional alloys, the three MEAs showed only negligible irradiation hardening and even softening in some cases. After irradiation, they exhibit somewhat surprising lattice constant reduction, and the microstructure contains small dislocation loops. Neither cavities nor precipitates were observed. This indicates that the MEAs have better irradiation resistance than traditional alloys, which can be attributed to the high-entropy and lattice distortion effect of MEAs.