Twisted bilayer graphene (TBG) exhibits fascinating correlation-driven phenomena like the superconductivity and Mott insulating state, with flat bands and a chiral lattice structure. We find by quantum-transport calculations that the chirality leads to a giant unidirectional magnetoresistance (UMR) in TBG, where the unidirectionality refers to the resistance change under the reversal of the direction of current or magnetic field. We point out that flat bands significantly enhance this effect. The UMR increases quickly upon reducing the twist angle, and reaches about 20% for an angle of 1.5° in a 10 T in-plane magnetic field. We propose the band structure topology (asymmetry), which leads to a direction-sensitive mean free path, as a useful way to anticipate the UMR effect. The UMR provides a probe for chirality and band flatness in the twisted bilayers.