The Hammers enter in the first qualifying round by virtue of topping the Fair Play League, and host the Andorran side in their first European tie in nine years.
New boss Slaven Bilic will not be taking the reins for the first time, but will watch from the stands as academy manager Terry Westley takes charge on Thursday.
West Ham face a long road to reach the group stage of the competition – if they see off Lusitans over two legs they’ll face two more qualifying rounds before a final play-off to enter the competition proper.
Westley has already revealed his team for Thursday evening’s encounter, and the Hammers have a mixture of youth and experience in their starting XI.
New signing Darren Randolph makes his debut in goal for the hosts, with youngsters Lewis Page and Reece Oxford also handed first-team debuts.
Diafra Sakho and Mauro Zarate lead a strong attack, while James Tomkins will captain the side from the centre of defence.
This will be the first-ever competitive meeting between an English and an Andorran side.
West Ham are making their first foray in to Europe since 2006-07, when they got knocked out of the UEFA Cup at the first round stage against Palermo.
West Ham have failed to find the net in each of their last four European matches.
FC Lusitans’ previous record in European qualifiers is W0 D1 L7; scoring just four goals and conceding 33.
Lusitans have conceded at least five goals in all four of their previous European qualifiers away from home.
Just one of the 46 European qualifying matches played by an Andorran side since 2008/09 has seen them pick up a victory.
West Ham are just 1/100 to kick off their Europa League campaign with a victory over rank outsiders FC Lusitans. 4-0 and 5-0 are consider the most likely scorelines in favour of the Hammers, who are considered 50/1 chances to win the competition, the same price as their Andorran visitors are just to win on the night. Diafra Sakho is the 9/4 favourite in the first goalscorer market followed by Mauro Zarate at 5/2, while Alfi Conteh is rated the visitors’ biggest threat at 18/1 to net first.