A new luminescent Zn(II)-based metal-organic framework (MOF), [Zn(TPOM)(NDC)]·3.5HO (Zn-MOF; TPOM = tetrakis(4-pyridyloxymethylene)methane and Hndc = 2,6-naphthalenedicarboxylic acid), was successfully synthesized by a hydrothermal reaction. The MOF exhibits excellent luminescence emission, and it can detect Fe(III) and Cr(VI) ions with high selectivity, well antiinterference performance, and short response time. In addition, Zn-MOF was selected as a parent coordination compound to encapsulate Eu cations to obtain a Eu-incorporated sample (Eu@Zn-MOF). Subsequently, we explored the potential application of Eu@Zn-MOF as a probe for the selective sensing of Fe(III) and Cr(VI) ions, and it revealed that we could differentiate Fe(III) and Cr(VI) ions by the combination Zn-MOF and Eu@Zn-MOF. More importantly, it represents the first example of MOF-based luminescent sensors which can detect and differentiate Fe(III) and Cr(VI) ions selectively. And the possible sensing mechanism was discussed in detail.