<p> The pandemic has exacerbated psychological and physical distress in vulnerable populations, including patients with advanced cancer. However, the full scope and nature of this distress in the post-pandemic era remains unclear. This study aimed to compare the psychological distress and physical symptom burden between two independent cohorts of patients with advanced cancer undergoing active treatment, assessed during versus after the COVID-19 pandemic. In a comparative cross-sectional design, two independent cohorts were evaluated: during-pandemic (<i>n</i> = 129; March-April 2020) and post-pandemic (<i>n</i> = 102; September 2023-February 2024) using HADS and ESAS. The prevalence of clinically significant anxiety was significantly lower in the post-pandemic cohort (35, 34%; 95% CI: 26.7–40.3%) compared to the during-pandemic cohort (54, 53%;95% CI: 46.7–62.9%; <i>p</i> = 0.021). In contrast, the prevalence of depression remained persistently high (43, 42% vs. 51, 50%; <i>p</i> = 0.57). The ESAS scores indicated that the symptoms were mild (with a range of 0 to 3) for both groups, and there were no significant differences in any of the items, including anxiety and depression. Although anxiety decreased after the pandemic, depression persisted. This underscores the need for sustained psychological monitoring in cancer survivorship care.</p>