Chemical immobilisation of pinnipeds is a routine procedure in research and veterinary practice. Yet, there are inevitable risks associated with chemical immobilisation, and the physiological response to anaesthetic agents in pinnipeds remains poorly understood. The current study used wearable continuous-wave near-infrared spectroscopy (NIRS) data from 10 trials of prolonged anaesthesia (0.5 to 1.4 h) induced through ketamine and midazolam in five grey seals (Halichoerus grypus) involved in other procedures. The aim of this study was to (1) analyse the effect of each compound on heart rate, arterial oxygen saturation (SpO2), and relative concentration changes in oxygenated [ΔO2Hb] and deoxygenated haemoglobin [ΔHHb] in cerebral tissue and (2) to investigate the use of NIRS as a real-time physiological monitoring tool during chemical immobilisation. Average group responses of ketamine (n = 27) and midazolam (n = 11) administrations were modelled using generalised additive mixed models (GAMM) for each dependent variable. Following ketamine and midazolam administration, [ΔHHb] increased and [ΔO2Hb] remained relatively stable, which was indicative of apnoea. Periods of apnoea were confirmed from respiratory band data, which were simultaneously collected during drugging trials. Given that SpO2 remained at 97% during apnoea, we hypothesized that increasing cerebral [ΔHHb] was a result of venous congestion as opposed to decreased oxygen delivery. Changes in heart rate were limited and appeared to be driven by the individual pharmacological actions of each drug. Future research could include simultaneous measures of metabolic rate, such as the relative change in concentration of cytochrome-c-oxidase, to guide operators in determining when apnoea should be considered prolonged if changes in [ΔHHb] and [ΔO2Hb] occur beyond the limits recorded in this study. Our findings support the use of NIRS as real-time physiological monitoring tool during pinniped chemical immobilisation, which could assist veterinarians and researchers in performing safe anaesthetic procedures.