Background/Objectives: Pembrolizumab demonstrates a high response rate in patients with mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC), with responses often sustained even after treatment cessation. However, the pathological complete response (pCR) rate in clinically responding cases remains unknown. This study aimed to evaluate the relationship between the radiological and pathological responses in patients with dMMR mCRC who responded to pembrolizumab. Methods: This retrospective study included 27 patients with dMMR mCRC treated with pembrolizumab. The radiological response was assessed using RECIST version 1.1 criteria. The pathological response was evaluated in patients who underwent metastasectomy, with pCR defined as the absence of residual cancer cells. Results: The median progression-free survival (PFS) of the cohort was 19 months. Among the 27 patients, 3 achieved clinical complete response (cCR), and 10 had clinical partial response (cPR), resulting in a response rate of 48%. All three patients with cCR maintained their responses without metastasectomy (2-year PFS: 100%). Among patients with cPR, eight maintained their responses, while two experienced progression (2-year PFS: 75%). Five patients with cPR underwent curative-intent metastasectomy, and four of them (80%) achieved pCR. Thus, at least 40% of patients with cPR in this cohort had no residual cancer histologically. Conclusions: Our findings demonstrate the significant discordance between the radiological and pathological responses to pembrolizumab in dMMR mCRC patients, with 80% of those with cPR achieving pCR upon metastasectomy. These observations highlight the need for improved response assessment methods for precision immunotherapy.