Mehdi Taremi (two), Kamaleddin Kamyabinia, Ramin Rezaeian, Masoud Shojaei (p) and Karim Ansari Fard all scored goals on the artificial pitch at the National Football Stadium in the tiny Pacific Ocean island.
The win lifted unbeaten Iran to 14 points, three clear at the top of the group standings, with two matches at home to India and Oman in March.
Iran had defeated Guam 6-0 in Tehran’s Azadi Stadium in early September.
Team Melli missed four players and two staff because of visa issues in the match against Guam.
Guam defender John Matkin was sent off after bringing down Taremi in the 51st minute in the penalty area.
Iran goalkeeper Alireza Beiranvand was also sent off after handling outside the area and taking out Guam striker Shane Malcolm in the 71st minute.