Online pharmacies are used less than other e-commerce sites in Germany. Shopping behavior does not correspond to consumption behavior, as online purchases are predominantly made for over-the-counter (OTC) medications. The objective of this study was to understand the purchasing experiences of online pharmacy customers in terms of critical factors for online pharmacy adoption. This study examined the perceived risk, perceived trust, and emotions related to purchasing medications online and, consequently, the purchase intention toward online pharmacies. In a within-subjects design (N=37 participants), 2 German online pharmacies with different perceptions of risk and trust were investigated for their main business, namely OTC and prescription drugs. The results of a preliminary study led to 1 online pharmacy with high and 1 with significantly low self-reported risk by the prestudy sample. Emotions were measured with a multimethod approach during and after the purchase situation as follows: (1) neural evaluation processes using functional near-infrared spectroscopy, (2) the automated direct motor response during the use of the online pharmacy via facial expression analysis (FaceReader), and (3) subjective evaluations through self-reports. Following the shopping experiences at both pharmacies for both product types, risk, trust, and purchase intention toward the pharmacies were assessed using self-assessments. The 2 online pharmacies were rated differently in terms of risk, trust, emotions, and purchase intention. The high-risk pharmacy was also perceived as having lower trust and vice versa. Significantly stronger negative emotional expressions on customers' faces and different neural activations in the ventromedial prefrontal cortex and dorsomedial prefrontal cortex were measured when purchasing prescription drugs from the high-risk pharmacy than from the low-risk pharmacy, combined with OTC medications. In line with this, customers' self-ratings indicated higher negative emotions for the high-risk pharmacy and lower negative emotions for the low-risk pharmacy. Moreover, the ratings showed lower purchase intention for the high-risk pharmacy. Using multimethod measurements, we showed that the preceding neural activation and subsequent verbal evaluation of online pharmacies are reflected in the customers' immediate emotional facial expressions. High-risk online pharmacies and prescription drugs lead to stronger negative emotional facial expressions and trigger neural evaluation processes that imply perceived loss. Low-risk online pharmacies and OTC medications lead to weaker negative emotional facial expressions and trigger neural evaluation processes that signify certainty and perceived reward. The results may provide an explanation for why OTC medications are purchased online more frequently than prescription medications.