Colombia's star striker, Radamel Falcao of Atletico Madrid, stayed on the bench throughout the game at the Miami Dolphins' Sun Life stadium.
Martinez opened the scoring in the 23rd minute, swooping after a Juan Cuadrado shot was parried out by Guatemala keeper Ricardo Jerez.
Porto forward Martinez then doubled the advantage, twisting and turning inside the box before firing past Jerez but the striker was replaced by Colombia coach Jose Pekerman as part of a series of changes in the second half.
Abel Aguilar made it 3-0 in the 56th minute and although a Jose Contrera penalty gave some cheer to the Guatemalan fans, Colombia restored their three-goal advantage with an 81st minute Luis Muriel header.
Colombia are currently third in South American qualifying, just a point behind second placed Ecuador and four behind leaders Argentina.
Pekerman's team are at home to Bolivia on March 22 and then visit Venezuela four days later.