The development of hypertension and heart failure is correlated with the hyperactivation of the sympathetic nervous system. Beta-blockers are often considered a good therapeutic option in such clinical scenarios. However, the choice of β-blocker is a concern because of certain aspects like associated metabolic disturbances with their usage. Metoprolol has been reported to have the potential to alleviate sympathetic overdrive in patients with hypertension and heart failure. S-Metoprolol is the chirally pure β-blocker with favorable pharmacological features, improved safety profile, and allied clinical advantages versus racemic metoprolol; given this, can it be an effective therapeutic option against sympathetic overdrive in patients with hypertension and/or heart failure is not fully recognized yet. In this review, we attempted to discuss the current facts around sympathetic overdrive linked with hypertension as well as heart failure and pertaining pharmacological intervention with a focus on β-blockers in these clinical situations with an emphasis on the likely beneficial role of S-metoprolol.