We aimed to study the effects of an ethyl acetate fraction of Physalis alkekengi (PAE) on d-galactose (d-gal)-induced senescence and the underlying mechanism. Firstly, analysis of the phytochemical composition revealed total flavonoids, total phenolics, total saponins, rutin, and luteolin contents of 71.72 ± 2.99 mg rutin equivalents/g, 40.19 ± 0.47 mg gallic acid equivalents/g, 128.13 ± 1.04 mg oleanolic acid equivalents/g, 1.67 ± 0.07 mg/g and 1.61 ± 0.01 mg/g, respectively. The mice were treated with d-gal for six weeks, and from the fifth week, the mice were administered with PAE by gavage once a day for five weeks. We found significant d-gal-induced ageing-related changes, such as learning and memory impairment in novel object recognition and Y-maze, fatigue in weight-loaded forced swimming, reduced thymus coefficient, and histopathological injury of the liver, spleen, and hippocampus. The PAE effectively protected from such changes. Further evaluation showed that PAE decreased the senescence-associated β-galactosidase of the liver, spleen, and hippocampus, as well as the oxidative stress of the liver, plasma, and brain. The abundance of flavonoids, phenols, and saponins in PAE may have contributed to the above results. Overall, this study showed the potential application of PAE for the prevention or treatment of ageing-associated disorders.