Limited by the insufficient active sites and the interference from breath humidity, designing reliable gas sensing materials with high activity and moisture resistance remains a challenge to analyze human exhaled breath for the translational application of medical diagnostics. Herein, the dual sensing and cooperative diagnosis is achieved by utilizing metal-organic frameworks (MOFs) and its derivative. The Fe-MIL-101-NH2 serves as the quartz crystal microbalance humidity sensing layer, which exhibits high selectivity and rapid response time (16 s/15 s) to water vapor. Then, the Co2+ and Ni2+ cations are further co-doped into Fe-MIL-101-NH2 host to obtain the derived Co/Ni/Fe trimetallic  oxides (CoNiFe-MOS-n). The chemiresistive CoNiFe-MOS-n sensor displays the high sensitivity (560) and good selectivity to acetone, together with a lower original resistance compared with Fe2O3 and NiFe2O4. Moreover, as a proof-of-concept application, synergistic integration of Fe-MIL-101-NH2 and derived CoNiFe-MOS-n is carried out. The Fe-MIL-101-NH2 is applied as moisture sorbent materials, which realize a sensitivity compensation of CoNiFe-MOS-n sensors for the detection of acetone (biomarker gas of diabetes). The findings provide an insight for effective utilization of MOFs and the derived materials to achieve a trace gas detection in exhaled breath analysis.