Increased rates of reactive oxygen/nitrogen species (ROS/RNS) are involved in almost all cancer types, associated with tumor development and progression, causing damage to biomolecules such as proteins, nucleic acids and membrane lipids, in different biological compartments. We used a human tumor xenograft mouse model to evaluate for the first time in parallel the remodeling of fatty acid moieties in erythrocyte membrane phospholipids and the level of ROS-induced DNA lesions in liver and kidney tissues. Using liquid chromatography tandem mass spectrometry the 5′R and 5′S diastereoisomers of 5′,8-cyclo-2′-deoxyadenosine and 5′,8-cyclo-2′-deoxyguanosine, together with 8-oxo-7,8-dihydro-2′-deoxyadenosine, were determined in mice at young (4- and 5-weeks) and old (17-weeks) ages and compared with control SCID mice without tumor implantation. Tumor-bearing mice showed a higher level of ROS-damaged nucleosides in genomic DNA as the age and tumor progress, compared to controls (1.07–1.53-fold in liver and 1.1–1.4-fold in kidney, respectively). The parallel fatty acid profile of erythrocyte membranes showed a profound lipid remodeling during tumor and age progression consisting of PUFA consumption and SFA enrichment (ca 28% and 58%, respectively, in late stage tumor-bearing mice), markers of enhanced oxidative and proliferative processes, respectively. Membrane lipid remodeling and ROS-induced DNA lesions may be combined to afford an integrated scenario of cancer progression and ageing, reinforcing a holistic vision among molecular markers rather than the biomarker identification in a single compartment.