Guided by the self‐penetrating features can improve the stability of metal organic frameworks (MOFs), an unprecedented 3D self‐penetrated framework, {[Zn (tptc)0.5(bimb)]·H2O}n (NUC‐6, here NUC corresponding to North University of China), with 3D (4,4)‐c {86} net, was designed. Benefit from the high chemical stability and excellent luminescent property, NUC‐6 can be act as an efficient multi‐response chemo‐sensor in detecting dichloronitroaniline pesticide and nitrofuran antibiotics in water with the detection limits are 116 ppb for DCN pesticide, 16 ppb for NFT antibiotic, and 12 ppb for NTZ antibiotic. Besides, the mechanisms of luminescence quenching were revealed from the viewpoint of internal filter effect (IFE) and photo‐induced electron transfer (PET), implied by the optical spectroscopy and quantum chemical calculation. This work provides a promising strategy to design stable MOFs by improving the self‐penetrating features and to expand their practical applications in the detection of organic pollutants in aqueous medium.