Signal regulatory protein alpha (SIRPα) is an essential immune checkpoint, predominantly expressed on myeloid cells, that binds to CD47. This interaction, termed the ‘don't eat me’ signal, contributes to immune suppression. Consequently, disruption of the SIRPα/CD47 axis emerges as a promising strategy to intervene in the ‘don't eat me’ signal, thereby initiating phagocytic activation. Various preclinical and clinical studies employed SIRPα/CD47‐targeting molecules to disrupt the SIRPα/CD47 axis to promote cancer phagocytosis. However, concerns regarding their limited efficacy and side effects pose a challenge to applying this approach to cancer therapy. Here, we investigated the role of the SIRPα/CD47 axis in phagocytosis by performing clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9‐mediated SIRPA gene disruption in the monocytic cell line THP‐1. The SIRPα knockout (KO) THP‐1 cells were comprehensively characterized for their phenotype and functions, including differentiation into M0 macrophages, polarization into M1 or M2 macrophages, and phagocytosis of bioparticles and cancer cells, and compared to their wild‐type (WT) counterparts. The SIRPα KO THP‐1 cells retained their monocyte and macrophage characteristics. Remarkably, they exhibited enhanced phagocytosis of bioparticles and leukemic cell lines but not breast cancer cell lines. The introduction of a chimeric antigen receptor (CAR) targeting tumor‐associated mucin1 antigen (tMUC1‐CAR) further enhanced their phagocytic activity against the breast cancer cell line, MCF‐7, which expresses high levels of MUC1. Our findings highlight the therapeutic potential of SIRPα KO macrophages in cancer immunotherapy, particularly for hematologic malignancies. However, a combination with CAR was necessary to enhance the phagocytic activity against solid cancer models.