Cachexia in cancer patients is a life-threatening wasting condition without any effective treatment options. This syndrome is ostensibly induced by multiple tumour-derived factors, although the relative contribution of these ‘tumourkines’ to the initiation and progression of cachexia has proven difficult to determine. Here, we used adeno-associated viral vectors (AAVs) to raise the circulating levels of two recognised tumourkines, interleukin-6 (IL-6) and/or activin A, in the absence of tumour burden. In this approach, we characterised their respective contribution to the pathogenesis of cachexia. Mice with elevated levels of IL-6 demonstrated substantial weight loss after nine weeks (-8.1% or -3.0 ± 1.0 g), and greater weight loss was observed in mice with high circulating activin A (-11% or -4.0 ± 1.4 g). Co-elevation of both serum IL-6 and activin A to levels approximating those observed in cachexia models induced a more rapid and profound weight loss in mice (-15.4%; -5.9 ± 1.8 g). Body composition analysis indicated that activin A primarily drove the loss of body weight from decreases in lean mass, while IL-6 was the major mediator of fat loss. Histological and transcriptional analysis of affected organs/tissues (skeletal muscle, fat and liver) identified interactions between the activin A and IL-6 signalling pathways. For example, activin A curbed the IL-6-induced acute phase response in liver, whereas IL-6 exacerbated the detrimental effects of activin A in skeletal muscle. Our new approach provides the means to deconstruct cachexia and to identify the tumourkines best targeted to slow/reverse this devastating condition.