Oral antibiotics are commonly prescribed to non-hospitalized adults. However, antibiotic-induced changes in the human gut microbiome are often investigated in cohorts with preexisting health conditions and/or concomitant medication, leaving the effects of antibiotics not completely understood. We used a combination of omic approaches to comprehensively assess the effects of antibiotics on the gut microbiota and particularly the gut resistome of a small cohort of healthy adults. We observed that 3 to 19 species per individual proliferated during antibiotic treatment and Gram-negative species expanded significantly in relative abundance. While the overall relative abundance of antibiotic resistance gene homologs did not significantly change, antibiotic-specific gene homologs with presumed resistance toward the administered antibiotics were common in proliferating species and significantly increased in relative abundance. Virome sequencing and plasmid analysis showed an expansion of antibiotic-specific resistance gene homologs even 3 months after antibiotic administration, while paired-end read analysis suggested their dissemination among different species. These results suggest that antibiotic treatment can lead to a persistent expansion of antibiotic resistance genes in the human gut microbiota and provide further data in support of good antibiotic stewardship. Abbreviation: ARG–Antibiotic resistance gene homolog; AsRG–Antibiotic-specific resistance gene homolog; AZY–Azithromycin; CFX–Cefuroxime; CIP–Ciprofloxacin; DOX–Doxycycline; FDR–False discovery rate; GRiD–Growth rate index value; HGT–Horizontal gene transfer; NMDS–Non-metric multidimensional scaling; qPCR–Quantitative polymerase chain reaction; RPM–Reads per million mapped reads; TA–Transcriptional activity; TE–Transposable element; TPM–Transcripts per million mapped reads.