They went down by 55 runs against a Fleetwood team who made it eight wins from eight to start the 2022 season.
Having won the toss, Morecambe chose to field first and reduced the home side to 60-3.
Atiq Uz-Zaman (18) was run out before Lewis Smith picked up the wickets of Charlie Clark (22) and Harry McAleer (11).
That brought together Declan Clerkin and Adam Sharrocks, both of whom scored half-centuries for the hosts.
They added 77 before Clerkin fell for a 43-ball 58, having struck a hat-trick of boundaries and sixes.
He fell to Irfan Qayyum, who also dismissed Sharrocks for 51, leaving Jeremy Davies 23 not out as Fleetwood posted 188-5.
Qayyum took 2-42 and Lewis Smith 2-44 for a Morecambe team who were all out for 133 in reply.
It was Fleetwood’s overseas amateur, Zac Corcoran, who struck early in removing Lewis Smith (3), Gareth Pedder (13) and Luke Pearson (9).
Clerkin also chipped in, picking up the wickets of Alex Briggs (5) and Reuben Orr (14) before a run out accounted for Lloyd Smith (1).
The rest of the innings was dominated by Jack Wilkinson as he saw off Shane Burton (8), Qayyum (23) and Stefan Dixon (8).
He then completed the match with the wicket of Jake Smith (7), leaving Ashton Ward 20 not out.
That gave Wilkinson figures of 4-29, Corcoran 3-37 and Clerkin 2-34.
Though Morecambe stayed second in the table, defeat leaves them on 63 points, 32 behind Fleetwood and level with third-placed Penwortham – and only six clear of Eccleston in seventh.
They will be looking to bounce back on Saturday with a home game against bottom club Croston (1pm).
The seconds, however, ended their long wait for a win in Division 1B as they beat Great Eccleston in the battle of the bottom two.
Morecambe had gone into the game bottom of the table after losing all of their first seven matches.
They posted a 42-run win at Woodhill Lane, where they made 204-5 with Andrew Creech hitting 82.
Great Eccleston’s reply saw them all out for 162, Dan Stanley claiming 4-37 and Jack Bird 3-33.