Psychological disparities impact physical activity and fitness in sedentary female college students by affecting cardiovascular efficiency. <i>Ganoderma lucidum</i>, vitality-enhancing herb alleviates health and rejuvenates the mind-body to improve endurance fitness. A double-blinded, randomized, placebo-controlled parallel design study was conducted to determine whether supplementation of <i>G. lucidum </i>in daily dosages of 500 mg (GL<sub>500mg</sub> group) and 1000 mg (GL<sub>1000mg</sub> group) improves psychophysiological health capabilities during the different phases of the experimental trial. Analysis for pre-experimental trial (day 0), experimental trial (day 15), and post-experimental trial (after day 30) on anthropometric, psychological, physiological, and physical fitness parameters were executed. Seventy-eight participants (<i>n</i> = 78, age 20.64 ± 3.21 years) were assigned randomly and equally divided (<i>n </i>= 26) to one of the three treatment groups for intragroup and intergroup comparisons. Significant differences in the post-experimental GL<sub>1000mg</sub> group for heart rate (HR), maximal oxygen consumption (VO<sub>2max</sub>), physical work capacity (PWC<sub>170</sub>), and right-hand grip strength (<i>P</i> < 0.05) compared with the placebo group were observed. GL<sub>1000mg</sub>-supplemented group also significantly improved (<i>P</i> < 0.05) HR, VO<sub>2max</sub> and PWC<sub>170</sub> (<i>P</i> < 0.001) after pre- to post-trials. Experimental trial between placebo and GL<sub>1000mg</sub> group and post-experimental trial between the GL<sub>500mg</sub> and GL<sub>1000mg </sub>group showed significant changes in VO<sub>2max</sub>(<i>P</i> < 0.001) and PWC<sub>170</sub> (<i>P</i> < 0.05). Anxiety, depression, vitality and positive well-being scores significantly improved, leading to improved psychological well-being after GL<sub>1000mg</sub> supplementation. GL<sub>1000mg</sub> supplementation for 30 days might act as a longevity-promoting tonic for endurance and strength performance by ameliorating stress to improve the overall psychophysiological health, vitality and quality of life for better cardiovascular efficacy.