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RAS‐MAPK signaling promotes immune evasion and cancer cell survival, and MAPK inhibitors (MAPKis) are frequently used as cancer therapies. Despite progress elucidating the direct effects of MAPKi on immune cells, their indirect effect on the tumor microenvironment (TME) through changes in tumor cells remains incompletely understood. Here, we present evidence of a rapid compensatory response to MAPKi that is driven by sustained p38 MAPK signaling and by which cancer cells can upregulate the immunosuppressive protein CD73 to reduce the antitumor immune response. This compensatory response also results in decreased sensitivity toward MAPKi, and, accordingly, combining anti‐CD73 antibodies and MAPKi significantly enhances the antitumor effect compared to single‐agent treatment in vivo. Combining MAPKi and anti‐CD73 was accompanied by significant alterations in intratumor immune cell composition, supporting the effect of MAPKi‐induced CD73 expression on the TME. We show that high CD73 expression significantly correlates with worse outcome in MAPKi‐treated colorectal cancer patients, highlighting the potential clinical importance of increased CD73 expression following MAPKi treatment. Our findings may explain the diminished effect of MAPKi in cancer patients and provides further rationale for combined anti‐CD73 and MAPKi treatment., RAS‐MAPK signaling promotes immune evasion and cancer cell survival, and MAPK inhibitors (MAPKis) are frequently used in cancer therapy. Here, we present evidence that RAS‐MAPK inhibition increased the expression of the immunosuppressive protein CD73 by a rapid adaptive bypass mechanism involving MAPK‐p38 signaling. Compensatory MAPK‐p38 signaling increased tumor cell growth during MAPKi treatment. Additionally, targeting of CD73 in vivo augmented MAPKi. High CD73 expression was associated with a worse outcome in RAS‐MAPKi‐treated patients with colorectal cancer (CRC), indicating that combined anti‐CD73 and MAPKi treatment could be beneficial for patients with CRC resistant to MAPKi therapy.