It is of extreme importance to reduce side eﬀects resulted from the nonspeciﬁc uptake of phototherapeutic agents by normal tissues. Currently, single responsive strategy still cannot entirely satisfy the requirements of practical applications. In this study, we developed one kind of combination-responsive phototherapeutic nanoplatforms, where oxygen deficient molybdenum oxide (MoO3-x) hybridized hyaluronic acid (HA) hollow nanospheres, namely MoO3-x@HA HNSs, were constructed via a facile one-step method. In MoO3-x@HA HNSs, the reasonable combination of actively targeted specificity endowed by HA component and tumor microenvironment-responsive phototherapy activity induced by MoO3-x component can effectively improve the precision of phototherapy. The results of in vitro and in vivo experiments confirm that MoO3-x@HA HNSs can selectively kill CD44-overexpressing cancer cells and inhibit tumor growth with irradiation from an 808 nm laser, revealing their remarkable synergistic photothermal therapy/photodynamic therapy effect with CD44 receptor-targeted specificity and pH-responsiveness in treating cancer. We also prove that MoO3-x@HA HNSs can be used as a contrast agent for the computed tomography/photoacoustic imaging imaging. Encouraged by these results, it is anticipated that the reasonable combination of active targeting and tumor microenvironment responsiveness can be promising strategy to develop phototherapeutic nanoplatforms for precise multi-modality cancer theranostics.