Alex were quickly out of the blocks - a deft pass by Byron Moore finding England Under-19 striker Clayton in the area where Shrimpers goalkeeper Paul Smith was out well to save with his legs, but the opening goal would soon arrive in some style.
Moore's corner from the right was stroked low towards the edge of the area from the right and Harry Davis dummied the pass for Murphy to steer into the top corner despite Anthony Straker's presence on the goal-line.
Moments later the whole ground stood and applauded in a pre-planned tribute to the family of absent Crewe defender Adam Dugdale, whose newborn son sadly passed away at the end of the week.
Shrimpers fans celebrated what they thought was the award of a penalty before the half hour when Britt Assombalonga tangled with Railwaymen defender Mark Ellis. Referee Nigel Miller correctly signalled for a goal-kick.
The Blues were by now asking regular questions of Crewe and should have been level nine minute before the break, but Mkandawire sent a free header over from Barker's corner.
That momentum was spurned early in the second half as Southend gifted Crewe their second.
Ryan Creswell played the ball into midfield when Mohsni was slow to react and bundled aside by Murphy before Chuks Aneke and Moore combined to leave Clayton with a tap-in.
Mohsni immediately looked to make amends but his header from point-blank range was superbly diverted away from the goalmouth by Davis.
Brown brought on Ben Reeves and Barry Corr for Barker and Mohsni before the hour and Corr headed wide when his fellow substitute played in Gavin Tomlin to cross, while Clayton arched a shot beyond the top corner as Crewe refused to rest on their laurels.
In the 73rd minute, Corr saw his header from Reeves' corner hacked off the line by Matt Tootle after Kelvin Mellor deflected his initial strike behind.
Southend's efforts took their toll and Smith produced a magnificent reaction save to keep out a wickedly deflected drive from Ryan Colclough before fellow sub Ajay Leitch-Smith rattled the crossbar in stoppage time.