Background: After the failure of transarterial chemoembolization (TACE) combined with first-line tyrosine kinase inhibitor therapy, the subsequent therapy for progressed hepatocellular carcinoma (HCC) patients is still controversial. This study was performed to evaluate the safety and efficacy of the subsequent combination of PD-1 inhibitors (TACE combined with first-line tyrosine kinase plus PD-1 inhibitors) relative to switching to the subsequent regorafenib (TACE plus regorafenib). Methods: The data of HCC patients who suffered from the failure of TACE combined with first-line tyrosine kinase inhibitor therapy from July 2019 to August 2022 were assessed in this single-center retrospective study. Primary study outcomes included progression-free survival (PFS) and overall survival (OS), while the secondary outcomes were treatment-related adverse events, disease control rate (DCR), and objective response rate (ORR). Results: We enrolled a final total of 113 patients, including 73 patients who received TACE combined with first-line tyrosine kinase and PD-1 inhibitors (Group 1) and 40 patients who received TACE plus regorafenib (Group 2). The OS in Group 1 (15.0; 95% confidence interval [CI], 9.8–20.1 months) was significantly higher compared to Group 2 (9.0; 95% CI, 6.6–11.3 months) (P = 0.016). The PFS in Group 1 (11.0; 95% CI, 8.4–13.5 months) was also significantly higher compared to Group 2 (6.0; 95% CI, 4.6–7.3 months) (P = 0.010). No significant between-group differences in the ORR (P = 0.562) and DCR (P= 0.202) were found; however, the percentage of patients with proteinuria in Group 1 was significantly lower compared to Group 2 (2.73% vs. 20.00%, P= 0.006). Conclusions: The subsequent combining PD-1 inhibitors after the failure of TACE plus first-line tyrosine kinase inhibitor (TACE combined with first-line tyrosine kinase plus PD-1 inhibitors) may be associated with improved OS and PFS compared with switching to the subsequent regorafenib (TACE plus regorafenib).