Mayorkas stood alongside president and first lady unmasked at outdoor ceremony at Capitol on Saturday
Mr Mayorkas is fully vaccinated and experiencing only mild symptoms.
Department spokesperson Marsha Espinosa said in a statement: “Secretary Mayorkas tested positive this morning for the Covid-19 virus after taking a test as part of routine pre-travel protocols.”
She continued: “Secretary Mayorkas is experiencing only mild congestion; he is fully vaccinated and will isolate and work at home per CDC protocols and medical advice. Contact tracing is underway.”
One of Mr Mayorkas’ most recent public events was on Saturday when he attended the National Peace officers’ Memorial Service at the US Capitol.
He stood unmasked alongside Joe Biden and Jill Biden at the event, which was held outdoors.
Both the president and first lady are fully vaccinated, and Mr Biden received a booster shot in late September.
On Friday, Mr Mayorkas attended a wreath-laying ceremony honouring Customs and Border Protection officers who lost their lives in the line of duty.
The Independent has asked the White House if the president and first lady will be taking any further precautions as a result of their potential exposure.
While breakthrough Covid infections are relatively rare for fully vaccinated people, they do happen, though they result in far fewer serious infections or complications, and fewer incidences of hospitalisation and death.
Data from the Centers for Disease Control and Prevention shows that people who are unvaccinated are 12 times more likely to be hospitalised and 11.3 times more likely to die from the virus than those who are vaccinated.