Jim Bentley's side welcome high-flying Bury after bowing out to Conference Premier side Dover Athletic, while Southend host rock-bottom Hartlepool United after being humbled by non-League Chester at Roots Hall.
Morecambe are now four without a win in all competitions and Bentley wants an immediate response to Saturday's "frustrating" trip to the south coast.
"We're not having a great time at the minute and we hadn't won in three before the game," he told the club's official website.
"But in the FA Cup a couple of sticky performances goes out of the window.
"It was a frustrating day for everyone, but we can't feel sorry for ourselves and we have to bounce back against Bury on Saturday."
Phil Brown's Southend have won just three times at home this term, something the former Hull City boss wants to improve on against struggling Hartlepool.
"We've got to reproduce our away form and bring it to Roots Hall to give the fans something to shout about," he said.
"We have to address it."
Exeter City face a tricky trip to Newport County on Sunday as they seek to bounce back from defeat to minnows Warrington Town while, at the summit, second-placed Luton Town can apply pressure on Wycombe Wanders when they host Tranmere Rovers.
Gareth Ainsworth's leaders travel to managerless Burton Albion on Monday and in-form Shrewsbury Town welcome Mansfield Town knowing they too have a chance of sitting top come the end of the weekend.
Dagenham and Redbridge and Carlisle United can pull further clear of danger when they face AFC Wimbledon and Accrington Stanley respectively, with Russ Wilcox targeting back-to-back York City wins against Oxford United.
Portsmouth travel to Plymouth Argyle in Saturday's early game, with the weekend's action beginning at the Abbey Stadium on Friday when Richard Money's Cambridge United entertain Northampton Town.
Elsewhere, Stevenage host a Cheltenham Town side buoyed by their 5-0 hammering of third-tier opponents Swindon Town in the FA Cup at the weekend.
