Background: Pickleball is one of the fastest growing sports, and the use of virtual reality is also fast growing. Because the physiological responses in real life (IRL) vs. virtual reality are unknown, the purpose of this research was to compare heart rate, metabolic and pulmonary measures IRL vs. mixed reality (MR) during pickleball activity. Methods: Eleven adult participants were outfitted with a portable metabolic unit, heart rate monitor, and virtual reality headsets. Participants played simulated pickleball for 5 min IRL and 5 min in MR. Dependent variables included average heart rate (HR [beats per minute (bpm)], ventilation (VE [L/min]), tidal volume (VT [L]), respiratory frequency (Rf [breaths per min]), respiratory exchange ratio (RER), percent of calories from fat (FAT%), percent of calories from carbohydrate (CHO%), energy expenditure (EE [kilocalorie (kcal]), and VO₂ (mL/kg/min). Data were analyzed using paired t-tests with significance accepted at p < 0.05. Effect size measurements were determined by interpretation of small (d = 0.2), medium (d = 0.5), and large (d = 0.8). Results: All metabolic and pulmonary variables except for FAT% were higher during IRL when compared with MR with effect sizes ranging from median to large. Conclusions: The results of this study provide evidence that playing pickleball IRL results in greater physiological responses in comparison to MR. Since MR demands less exertion and substrate use than IRL this result can be beneficial for training purposes with the added potential of reduced injury.