It is the first time the ports have been connected by a scheduled ferry service.
From 25 June to 18 July, Stena Line will sail at weekends between the two ports. In normal times, Holyhead has only one route, to Dublin.
The ferry firm also links Belfast with Liverpool and Cairnryan in southwest Scotland.
Strict Irish rules on arrivals from the UK because of concerns about the so-called Delta variant have dampened demand for transport to and from the republic.
Stena Line says it is “currently experiencing very high demand on its Belfast routes” and that the new link “will provide much-needed additional capacity to and from Northern Ireland”.
Stena Estrid will sail from Holyhead at 11.30pm on Friday and Saturday nights, arriving at Belfast at 7.45am the following day.
The likely sailing distance is around 120 miles, compared with 75 miles between Holyhead and Dublin.
The return journey will depart from Belfast at 9.30am and arrive at Holyhead at 4pm.
Fares start at £22 for a foot passenger and £130 for a car plus driver.
The firm’s trade director (Irish Sea), Paul Grant, said: “The much-anticipated summer rebound for travel is beginning and we are hugely encouraged by current booking trends.”
A planned air link between Belfast City airport and Cardiff has been scuppered by the collapse of Stobart Air, which was to have operated the route on behalf of Aer Lingus Regional.