Abstract Caffeine is a widely used drug that broadly affects human cognition and brain function. Caffeine acts as an antagonist to the adenosine receptors in the brain. Previous anecdotal reports have also linked caffeine intake with changes in pupil diameter. By modifying the retinal irradiance, pupil diameter modulates all ocular light exposure relevant for visual (i.e., perception, detection and discrimination of visual stimuli) and non-visual (i.e., circadian) functions. To date, the extent of the influence of caffeine on pupillary outcomes, including pupil diameter, has not been examined in a systematic review. We implemented a systematic review laid out in a pre-registered protocol following PRISMA-P guidelines. We only included original research articles written in English reporting studies with human participants, in which caffeine was administered, and pupil diameter was measured using objective methods. Using broad search strategies, we consulted various databases (PsycINFO, Medline, Embase, Cochrane Library, bioRxiv and medRxiv) and used the Covidence platform to screen, review and extract data from studies. After importing studies identified through database search (n = 517 imported, n = 46 duplicates), we screened the title and abstracts (n = 471), finding 14 studies meeting our eligibility criteria. After full-text review, we excluded seven studies, leaving only a very modest number of included studies (n = 7). Extraction of information revealed that the existing literature on the effect of caffeine on pupil parameters is very heterogeneous, differing in pupil assessment methods, time of day of caffeine administration, dose, and protocol timing and design. The evidence available in the literature does not provide consistent results but studies rated as valid by quality assessment suggest a small effect of caffeine on pupil parameters. We summarize the numeric results as both differences in absolute pupil diameter and in terms of effect sizes. More stud Previous anecdotal reports have also linked caffeine intake with changes in pupil diameter. By modifying the retinal irradiance, pupil diameter modulates all ocular light exposure relevant for visual (i.e., perception, detection and discrimination of visual stimuli) and non-visual (i.e., circadian) functions. To date, the extent of the influence of caffeine on pupillary outcomes, including pupil diameter, has not been examined in a systematic review. We implemented a systematic review laid out in a pre-registered protocol following PRISMA-P guidelines. Caffeine has been shown to impact circadian rhythms and sleep behaviour in human and animal studies [ 5 – 8 ]. Previous research has shown that caffeine may potentiate non-image-forming effects of light in animals and humans, for instance, on the timing of rest-activity cycles or on melatonin secretion [ 9 – 13 ]. Therefore, caffeine may represent a tool to enhance light effects on the biological clock. The pupil acts as a gate regulating the amount of light entering the eye, thereby modifying light information at the earliest stage. The pupil diameter, which undergoes changes with age [ 14 – 19 ] and is linked to other ocular functions through the near triad involving vergence and accommodation [ 20 ], adjusts to environmental light through the pupillary light reflex (PLR). The PLR is controlled by the sympathetic and parasympathetic nervous system [ 21 – 23 ] and is therefore influenced by a range of inputs, including mental load, mood and alertness [ 19 ]. By stimulating the release of catecholamines, caffeine can increase activity in this autonomic nervous system. Acute caffeine and caffeine metabolites can promote the synthesis, release and turnover of central noradrenaline (NE) [ 24 – 27 ], e.g., in the locus coreuleus (LC) [ 24 ] and the brainstem [ 25 ]. LC-NE activity in turn increases pupil size and affects its response to light [ 22 , 23 , 28 ]. Therefore, it is reasonable that the stimulant properties of caffeine could potentially modulate pupil regulation. In the eye, the intrinsically photosensitive ganglion cells (ipRGCs) in the human retina represent the “front end” of the circadian system. The ipRGCs express the short-wave sensitive photopigment melanopsin [ 29 – 31 ]. A potential influence on pupil diameter could explain why caffeine has the potential to enhance light effects on the circadian system. In this systematic review, we focus on whether caffeine intake affects pupil control in humans, closing a critical gap in the literature. Methods Pre-registration and reporting guidelines The protocol for the systematic review in hand was registered on the Open Science Framework (OSF; https://osf.io/a5ymd/ ) [ 34 ]. We followed the PRISMA-P guidelines (2020) [ 35 ] for systematic reviews. Selection criteria We conducted a systematic literature search to evaluate the effects of caffeine intake on pupil control in humans. Conclusion In conclusion, the systematic review aimed to explore the potential impact of acute caffeine intake on pupil control in humans, filling a crucial gap in the existing literature. The findings from the included studies exhibit a lack of consistency and conclusive evidence regarding the effects of caffeine on pupil diameter. Methodological variations, small sample sizes, and confounding factors limit the available data. While some studies suggest a possible association between caffeine intake and pupil dilation, the results are not robust enough to draw firm conclusions. To address these limitations and provide more conclusive insights, future research should focus on well-designed randomised controlled trials with larger sample sizes, using consistent caffeine doses and administration methods. Attention should be given to minimising confounding variables, such as prior caffeine consumption and withdrawal effects, to isolate better the true effects of acute caffeine intake on pupil control. Incorporating modern pupillometric