Slow breathing exercises are a key component to many mind-body practices and have been shown to reduce blood pressure acutely. Long-term effects on blood pressure and autonomic tone are not well documented. We studied 99 healthy participants (41 ± 4 years, 76% female) who performed slow breathing exercises for 12 weeks and examined the effect of slow breathing on systolic blood pressure, diastolic blood pressure, and autonomic tone. At baseline average BP was 105 ± 11/67 ± 8 mmHg. Among the 11 participants with elevated blood pressure, BP was 126 ± 11.0/ 80 ± 5 mmHg. SBP and DBP decreased significantly (-2.4 ± 7.3 and − 1.6 ± 5.5 mmHg, respectively) at 12 weeks among all participants. Blood pressure among slow breathing participants with elevated baseline SBP > 120 mmHg and/or DBP > 90mmHg reduced further ( -10.3 ± 7.9 and − 3.8 ± 5.5 mmHg, respectively). In our regression model, baseline SBP was associated with further decreases in SBP from baseline to 12 weeks. No significant changes were observed from baseline to 12 weeks in autonomic tone as measured with spectral analyses, catecholamines, standing stress test, respiratory sinus arrhythmia, and Valsalva maneuver. Nor were there any observed correlations between changes in blood pressure and autonomic tone. In conclusion, 12-weeks of slow breathing exercises resulted in clinically significant reduction of blood pressure in the absence of statistically significant changes in autonomic tone. Further research into the mechanisms of slow breathing on blood pressure regulation and efficacy for hypertension.