DNA-RNA hybrid (DRH) duplexes are important intermediates in molecular biology and can play critical roles in the cell life. The flexibility of DRH duplexes can be important for their biological functions and may be very different from those of DNA and RNA duplexes. Here, we performed microsecond molecular dynamics simulations to quantitatively characterize the flexibility of DRH duplex in stretching and twist-stretch coupling. We found that a DRH duplex exhibits an intermediate conformation between A- and B-forms and closer to A-form. Furthermore, a DRH duplex has a stretch modulus of 834±34pN and a weak twist-stretch coupling. Such different flexibility of DRH duplex from DNA and RNA duplexes in stretching and twist-stretch coupling is mainly attributed to its different base-pair inclination.