Steve Bruce had made sweeping changes with record signings Nikica Jelavic and Shane Long ineligible, so Fryatt and Danny Graham led the attack while goalkeeper Steve Harper came into the side along with the likes of Abdoulaye Faye and David Meyler.
The Barclays Premier League team, though, had more than enough quality to see them through, with the Shrimpers - going well in the promotion race - restricted to a few chances, the best falling to striker Barry Corr.
The heavy rain in Essex had made the Roots Hall pitch very heavy and there was an early robust challenge from Corr on Yannick Sagbo, which earned him a swift yellow card from referee Lee Mason.
Despite such a different side of nine changes from the last Premier League game at Norwich, which they lost 1-0, Hull soon settled and started to take control of midfield.
Southend striker Corr, though, continued to cause the visitors defence a few problems as the centre-backs struggled to keep their footing at times.
On 23 minutes, defender Faye upended Anthony Straker just inside the Hull half and was straight into the referee's notebook.
Harper produced a fine save at point-blank range to turn over a bullet header from Corr after a long throw into the Hull penalty area.
Hull should have been ahead on 34 minutes.
George Boyd beat the offside trap down the left and centred to Graham for what looked a tap-in. However, the striker - on a first apprearance since New Year's Day - scuffed his shot straight at the keeper.
Faye's header from Boyd's curling free-kick was also saved and Southend's defence produced a last-ditch saving tackle on Fryatt in the six-yard box as the Premier League side finished the first half in the ascendancy.
Southend almost went into the lead at the start of the second half when a 30-yard strike from Michael Timlin crashed against the crossbar and Corr's follow-up header was straight at the keeper.
On 57 minutes, Graham's angled drive from Boyd's pass was saved at the near post before 20-year-old Daniel Bentley got down to boot away a deflected 18-yard effort from Meyer.
The goal eventually arrived on 62 minutes when Fryatt latched on to a loose ball in a crowded box to drive a low effort into the bottom right corner.
Robbie Brady came on for Graham after 73 minutes as Tigers boss Steve Bruce looked to freshen up his frontline. Midfielder Quinn was then unfortunate not to get on the end of Boyd's left-wing cross after arriving on the break at the far post.
Brady's low 20-yard effort was turned away off what was now a slick surface.
Southend pressed in the closing stages, played out during heavy rain, but other than a couple of scrambles in the Hull area as Corr fired over, they never really threatened to force a replay.
Fryatt made sure of progress when he cracked home a second in stoppage time after collecting a ball down the right and cutting in at the near post.