The coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains an extant threat against public health on a global scale. Cell infection begins when the spike protein of SARS-CoV-2 binds with the human cell receptor, angiotensin-converting enzyme 2 (ACE2). Here, we address the role of tetracycline as an inhibitor for the receptor-binding domain (RBD) of the spike protein. Targeted molecular investigation show that tetracycline binds more favorably to the RBD (-9.40 kcal/mol) compared to doxycycline (-8.08 kcal/mol), chloroquine (-6.31 kcal/mol), or gentamicin (-4.83 kcal/mol) while inhibiting attachment to ACE2 to a greater degree (binding efficiency of 2.98 kcal/(mol nm ) for tetracycline-RBD, 5.16 kcal/(mol nm ) for doxycycline-RBD, 5.59 kcal/(mol nm ) for chloroquine-RBD, and 7.02 kcal/(mol nm ) for gentamicin-RBD. Stronger inhibition by tetracycline is verified with nonequilibrium PMF calculations, for which the tetracycline-RBD complex exhibits the lowest free energy profile along the dissociation pathway from ACE2. Tetracycline binds to tyrosine and glycine residues on the viral contact interface that are known to modulate molecular recognition and bonding affinity. These RBD residues also engage in significant hydrogen bonding with the human receptor ACE2. The ability to preclude cell infection complements the anti-inflammatory and cytokine suppressing capability of tetracycline; this may reduce the duration of ICU stays and mechanical ventilation induced by the coronavirus SARS-CoV-2.