The summer signing from Ebbsfleet opened the scoring after 20 minutes with his first goal in a Shrimpers shirt and then turned provider for the second, teeing up Matt Harrold to scored from close range.
Aidy Boothroyd always ran the risk of an upset by making 11 changes to the side he fielded against Leicester City on Saturday, but he will be disappointed that his second string side failed to reach the heights they scaled against Gillingham in the last round.
The Hornets most potent attacking weapon was Anthony McNamee, the star of the last round. The diminutive winger forced Southend skipper Adam Barrett to head over his own bar, had Darryl Flahavan back-pedalling to tip over a rising drive and then teed up Tamas Priskin to shoot straight at the Southend number one in the first half.
Flahavan was by the far the busier of the two keepers but it was Richard Lee, the visitors custodian, who was picking the ball out of the net on 20 minutes. A defence-splitting pass from Franck Moussa sent MacDonald clear and he outpaced Matt Jackson and shot across Lee and into the far corner.
The goal did wonders for MacDonald's confidence and he showed great awareness to cut the ball back for Harold, his striker partner, on 54 minutes.
Harold and MacDonald posed a real threat to the Hornets and they almost added to their tally on 71 minutes. Harold was denied by an excellent recovery tackle from Cedric Avinel while MacDonald saw an effort beaten away by Lee.