2D nanomaterials have attracted considerable research interest in drug delivery systems, owing to their intriguing quantum size and surface effect. Herein, Gd3+-doped monolayered-double-hydroxide (MLDH) nanosheets are prepared via a facile bottom-up synthesis method, with a precisely controlled composition and uniform morphology. MLDH nanosheets as drug carrier are demonstrated in coloading of doxorubicin and indocyanine green (DOX&ICG), with an ultrahigh drug loading content (LC) of 797.36% and an encapsulation efficiency (EE) of 99.67%. This is, as far as it is known, the highest LC level at nearly 100% of EE among previously reported 2D drug delivery systems so far. Interestingly, the as-prepared DOX&ICG/MLDH composite material shows both pH-controlled and near-infrared-irradiation-induced DOX release, which holds a promise in stimulated drug release. An in vivo dual-mode imaging, including near-infrared fluorescence and magnetic resonance imaging, enables a noninvasive visualization of distribution profiles at the tumor site. In addition, in vitro and in vivo therapeutic evaluations demonstrate an excellent trimode synergetic anticancer activity and superior biocompatibility of DOX&ICG/MLDH. Therefore, MLDH nanosheets provide new perspectives in the design of multifunctional nanomedicine, which shows promising applications in controlled drug delivery and cancer theranostics.