Introduction: Caffeine, the most widely consumed psychoactive drug globally, has been associated with vascular changes in various organs, including the retina. Researchers have reported vascular constriction in the retina in response to caffeine, although data on its effects remain limited and somewhat contradictory. Further research is needed to clarify the specific impact of caffeine on retinal blood vessels and its potential implications for ocular health. Purpose: To investigate the effects of 200 mg of caffeine on systolic and diastolic blood pressure (SBP and DBP) and retinal vessel density (VD) assessed by optical coherence tomography angiography (OCTA). Methods: Prospective randomized, double-blind placebo-controlled, IRB-approved study in 59 healthy low caffeine users (< 136 mg of caffeine daily). Baseline 3 × 3 and 6 × 6 mm OCTA scans centered on the fovea as well as a 6 × 6 mm scans centered on the optic nerve head (ONH) were obtained. Participants were randomly assigned into caffeine group (CG, n = 42) receiving 200 mg caffeine pill or placebo group (PG, n = 17). OCTA scans were repeated at 60 and 120 min after intervention. VD was measured with Advanced Retina Imaging (ARI) network software (Carl Zeiss Meditec, Dublin, CA) for superficial capillary plexus (SCP) and deep capillary plexus (DCP). SBP/DBP readings were recorded before each imaging session. Ordinary one-way analysis of variance (ANOVA) of each group was performed using GraphPad Prism Version 9.3.0. Results: Both groups had comparable demographics and OCTA parameters at baseline. Two hours after intervention, the CG had a significantly higher SBP (123 ± 7 mmHg) and DBP (81 ± 5 mmHg) compared to the control group (118 ± 7 mmHg, 77 ± 6 mmHg) (p value = 0.012, 0.023). Regarding the OCTA VD metrics, there were no significant differences in VD between the caffeine and placebo groups, regardless of whether the scans were centered on the macula or ONH. Additionally, the comparison across different OCTA scan modalities, specifically the 3 × 3 mm and 6 × 6 mm scans, showed no discernible differences among groups. Conclusion: In conclusion, 200 mg of caffeine elevated blood pressure after 2 h but did not impact the retinal VD. This underscores the intricate relationship between caffeine, blood pressure, and retinal vascular dynamics, prompting further exploration of their implications for ocular health, especially in subjects with vascular disease.