Understanding the evolution of SARS-CoV-2 virus in various regions of the world during the Covid19 pandemic is of the utmost importance to help mitigate the effects of this devastating disease. We describe the phylogenomic and population genetic patterns of the virus in Mexico during the pre-vaccination stage, including asymptomatic carriers. Our RT-qPCR screening and phylogenomics directed a sequence/structure analysis of the Spike glycoprotein, revealing mutation of concern E484K in genomes from central Mexico, in addition to the nationwide prevalence of the imported variant 20C/S:452R (B.1.427/9). Overall, the detected variants in Mexico show mutations in the N-terminal domain (i.e., R190M), in the receptor-binding motif (i.e., T478K, E484K), within the S1-S2 subdomains (i.e., P681R/H, T732A), and at the basis of the protein, V1176F, raising concerns about the lack of phenotypic and clinical data available for the postulated variants of interest (VOIs) 20B/478K.V1 and P.3. Moreover, the population patterns of Single Nucleotide Variants (SNVs) from symptomatic and asymptomatic carriers sampled with a self-sampling scheme, revealed a bimodal distribution of polymorphisms in all three sampled localities from central Mexico, and confirmed the presence of several fixed variants, mostly from the 241T-3037T-14408T-23403G haplotype common in Asia. Despite gene flow among Mexican localities, we found differences in both the allelic frequencies among localities and the allelic imbalance of the mutation S194L of the nucleocapsid protein between symptomatic and asymptomatic carriers. Our results highlight the dual role of Spike and Nucleocapsid proteins in adaptive evolution of SARS-CoV-2 to their hosts and provide a baseline for specific follow-up of mutations of concern during the vaccination stage in Mexico.