The Zika virus (ZIKV) epidemic in the Americas established ZIKV as a major public health threat and uncovered its association with severe diseases, including microcephaly. However, genetic epidemiology in some at-risk regions, particularly Central America and Mexico, remains limited. We report 61 ZIKV genomes from this region, generated using metagenomic sequencing with ZIKV-specific enrichment, and combine phylogenetic, epidemiological, and environmental data to reconstruct ZIKV transmission. These analyses revealed multiple independent ZIKV introductions to Central America and Mexico. One introduction, likely from Brazil via Honduras, led to most infections and the undetected spread of ZIKV through the region from late 2014. Multiple lines of evidence indicate biannual peaks of ZIKV transmission in the region, likely driven by varying local environmental conditions for mosquito vectors and herd immunity. The spatial and temporal heterogeneity of ZIKV transmission in Central America and Mexico challenges arbovirus surveillance and disease control measures. Display omitted •Zika virus was introduced from Brazil to Central America via Honduras in summer 2014•Undetected spread to other Central American countries and Mexico occurred from late 2014•Genetic and epidemiological data indicate biannual peaks of transmission•Local variation in vector abundance could explain the biannual trend of transmission Thézé et al. examine the genomic epidemiology of Zika virus in Central America and Mexico. Following its likely introduction to Honduras in 2014, the virus spread undetected in the region. Genetic and epidemiological data indicate that biannual transmission peaks occurred, and could potentially be explained by local variation in mosquito abundance.