Doxorubicin(DOX) is a highly effective anticancer agent that improved survival and patient’s quality of live but causes dose-dependent cardiotoxic effects leading to severe and irreversible cardiomyopathy in many patients. Different preventive strategies, such as physical exercise and β-blockers, have been proposed to maintain physiological homeostasis. However, besides the extensive research that has been done to understand the mechanism and pathophysiology of DOX, it is not clear what is the most effective preventive approach to maintaining physiological homeostasis.    In the present work, we intended to compare the efficacy of two different approaches, one pharmacological intervention, using atenolol, a β1-selective antagonist, and other non-pharmacological intervention using treadmill training in an animal model of DOX. Female Wistar rats were divided into 4 groups: Doxorubicin (DOX; ip. cumulative dose 8mg/kg, 1 time/week, for 4weeks), DOX with physical exercise (DOX + EX; treadmill, 22 cm/seg for 30minutes, 5 times/week), DOX with β-blocker (DOX + ATN: DOX; ip. cumulative dose 8mg/kg, 1 time/week and 4mg/ml, Atenolol; oral administration, 5 times/week, for 4weeks) and controls (ip. with saline solution). At the end of the protocol, animals were anaesthetised with sodium pentobarbital and blood pressure(BP), electrocardiogram, heart rate(HR) and respiratory frequency(RF) were recorded. Baro and chemoreceptor reflexes were stimulated by phenylephrine(25µg/mL,iv) and lobeline(25µg/mL,ia), respectively and baroreflex gain and chemoreflex sensitivity calculated. Low frequencies(LF) and high frequencies(HF) were determined for sympathetic and parasympathetic activity estimation. One-way ANOVA with Tukey’s multiple comparison between means were used (significance p<0.05) for statistical analysis. All the experimental procedures were in accordance with the European Community legislation on animal experimentation and were approved by Ethical Committee of the Academic Centre of Lisbon. Our results reveal that DOX treatment triggered a significant decrease in systolic (CTL: 156±6 vs DOX: 114±9mmHg), diastolic (CTL: 105±3 vs DOX: 83±8mmHg) and mean BP (CTL: 127±3 vs DOX: 97±9mmHg) as well as in HR (CTL:378±24 vs DOX: 289±28bpm), caused hypopnea (CTL: 71±2 vs DOX: 41±3cpm), decreased baro (CTL: 1.5±0.3 vs DOX: 0.4±0.1bpm/mmHg) and chemoreflexes (CTL: 22±2 vs DOX:18±3cpm), without evidence of sympatho-excitation (LF-band, CTL: 2.93±0.9 mmHg2 vs DOX: 0.65±0.17 mmHg2). These changes can be explained by the decline in cardiac function, respiratory muscle weakness, autonomic dysfunction and vascular changes induce by DOX. During treatment with DOX, the physical activity protocol countered some of the adverse effects caused by DOX. It normalized systolic (165±5 mmHg), diastolic (123±6 mmHg) and mean BP (141±5 mmHg), HR (406±6 bpm), and RF (65±4 cpm) to physiological values and decreases the loss in baroreflex gain (0.5±0.06 bpm/mmHg). Chemoreflex sensitivity, sympathetic and parasympathetic activities remained similar.  Atenolol treatment, similar to the physical activity effect, also increased baroreflex gain (0.9±0.2 bpm/mmHg) and RF (70±4 cpm) to normal values, causing a clear tendency to maintain BP values. Although complementary data is still needed, with these results we can conclude that treadmill training was more effective than atenolol in counteracting the adverse effects of the cumulative low dose of DOX administered, suggesting that physical activity is a good non-pharmacological alternative to atenolol for preserving the homeostasis during DOX therapy.