SIGNIFICANCE: Transcranial photobiomodulation (tPBM) is an optical intervention that effectively enhances human cognition. However, limited studies have reported the effects of tPBM on electrophysiological brain networks. AIM: We aimed to investigate the site- and electroencephalogram (EEG)-frequency-specific effects of 800-nm prefrontal tPBM on the EEG global network topology of the human brain, so a better understanding of how tPBM alters EEG brain networks can be achieved. APPROACH: A total of 26 healthy young adults participated in the study, with multiple visits when either active or sham tPBM interventions were delivered to either the left or right forehead. A 19-channel EEG cap recorded the time series before and after the 8-min tPBM/sham. We used graph theory analysis (GTA) and formulated adjacency matrices in five frequency bands, followed by quantification of normalized changes in GTA-based global topographical metrics induced by the respective left and right tPBM/sham interventions. RESULTS: Statistical analysis indicated that the effects of 800-nm prefrontal tPBM on the EEG global topological networks are both site- and EEG-frequency-dependent. Specifically, our results demonstrated that the left 800-nm tPBM primarily enhanced the alpha network efficiency and information transmission, whereas the right 800-nm tPBM augmented the clustering ability of the EEG topological networks and improved the formation of small-worldness of the beta waves across the entire brain. CONCLUSIONS: The study concluded that 800-nm prefrontal tPBM can enhance global connectivity patterns and information transmission in the human brain, with effects that are site- and EEG-frequency-specific. To further confirm and better understand these findings, future research should correlate post-tPBM cognitive assessments with EEG network analysis.