BackgroundThe clinical translation of proton minibeam radiation therapy (pMBRT) presents significant challenges, particularly in developing an optimal treatment planning technique. A uniform target dose is crucial for maximizing anti‐tumor efficacy and facilitating the clinical acceptance of pMBRT. However, achieving a high peak‐to‐valley dose ratio (PVDR) in organs‐at‐risk (OAR) is essential for sparing normal tissue. This balance becomes particularly difficult when OARs are located distal to the beam entrance or require patient‐specific collimators.PurposeThis work proposes a novel pMBRT treatment planning method that can achieve high PVDR at OAR and uniform dose at target simultaneously, via multi‐collimator pMBRT (MC‐pMBRT) treatment planning method with joint dose and PVDR optimization (JDPO).MethodsMC‐pMBRT utilizes a set of generic and premade multi‐slit collimators with different center‐to‐center distances and does not need patient‐specific collimators. The collimator selection per field is OAR‐specific and tailored to maximize PVDR in OARs while preserving target dose uniformity. Then, the inverse optimization method JDPO is utilized to jointly optimize target dose uniformity, PVDR, and other dose‐volume‐histogram based dose objectives, which is solved by iterative convex relaxation optimization algorithm and alternating direction method of multipliers.ResultsThe need and efficacy of MC‐pMBRT is demonstrated by comparing the single‐collimator (SC) approach with the multi‐collimator (MC) approach. While SC degraded either PVDR for OAR or dose uniformity for the target, MC provided a good balance of PVDR and target dose uniformity. The proposed JDPO method is validated in comparison with the dose‐only optimization (DO) method for MC‐pMBRT, in reference to the conventional (CONV) proton RT (no pMBRT). Compared to CONV, MC‐pMBRT (DO and JDPO) preserved target dose uniformity and plan quality, while providing unique PVDR in OAR. Compared to DO, JDPO further improved PVDR via PVDR optimization during treatment planning.ConclusionA novel pMBRT treatment planning method called MC‐pMBRT is proposed that utilizes a set of generic and premade collimators with joint dose and PVDR optimization algorithm to optimize OAR‐specific PVDR and target dose uniformity simultaneously.