Abstract Background Patients should get actively involved in the management of their illness. The aim of this study was to assess the influence of lifestyle factors, including sleep, diet, and physical activity, on lithium levels in patients with bipolar disorder. Methods A multicenter study was performed. In total, 157 lithium measurements were done biweekly in a sample of 65 patients (35 women) over 6 weeks. Lifestyle, based on total sleep hours and physical activity, was assessed by actigraphy. Diet was evaluated using the Mediterranean Lifestyle Index (Medlife). Results 35.4% of patients had a normal weight. The mean Medlife score was 14.5 (± 2.5) (moderate-good adherence to Mediterranean diet). BMI, daily dose of lithium and intensity of physical activity had a combined effect on lithium levels, after adjustment for other variables. Patients who practiced intense physical exercise, who took lower doses and had a higher BMI exhibited lower levels of lithium. Conclusions Higher physical activity and BMI contribute to lower lithium levels. Patients should be made aware of these relationships to improve their perception of control and self-management. Lifestyle-based interventions contribute to establishing a more personalized medicine.