Limited research focused on exploring personal cooling garments (PCGs) that offer excellent portability, along with a substantial, long-lasting, and consistent cooling effect for healthcare workers exposed to extreme heat while combating the COVID-19 pandemic. To address this gap, a novel, energy-efficient, and portable semiconductor liquid cooling garment (SLCG) was introduced, which incorporates a semiconductor-powered cold source and a cooling vest crafted from a semi-transparent thermoplastic polyurethane (TPU) film that offers extensive body coverage. Its practical cooling efficacy was assessed through a human trial involving ten male participants engaging in two protocols under a hot-humid environment (i.e., 30 ± 0.5 °C, RH = 80 ± 5 %). These protocols included both low-intensity (Prot.1) and moderate-intensity (Prot.2) exercises, mimicking the physical demands faced by healthcare workers. SLCG significantly reduced the mean, torso and local skin temperatures during both Prot.1 and Prot.2 (p < 0.05), also with a notable reduction in heart rate and sweat loss during Prot.1 (p < 0.05). Rating of perceived exertion as well as thermal sensations, wetness sensations and comfort sensations in the whole-body and local-body (i.e., head & neck, trunk, arms and legs) were all remarkably improved using SLCG during Prot.1 (p < 0.05). These perceptual sensations in SLCG were only improved in the whole body during the resting stage, and in the trunk region during Prot.2 (p < 0.05). Furthermore, participants felt no significant added weight or movement restrictions with SLCG in either protocol.