This is a non-randomized, open-label, Phase Ib study of atezolizumab in combination with immunomodulatory agents for the treatment of participants with AML (relapsed/refractory and treatment-naive, elderly participants unfit for induction chemotherapy). The study has been designed with the intent, over time, to study multiple combinations of atezolizumab with different immunomodulatory agents in participants with AML. The study will begin with the evaluation of the combination of atezolizumab and guadecitabine (Arm A). In the future, additional arms may be added.

Inclusion Criteria:

• Life expectancy of at least 12 weeks
• Diagnosis of AML per World Health Organization criteria
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2
• Specifically, for participants in Cohorts A1 and A2: Age greater than or equal to (>=) 18 years, disease progression or failure to achieve complete or partial response after intensive cytotoxic therapy, participants cannot have received more than two prior intensive regimens (e.g., induction + consolidation and one salvage therapy + consolidation)
• Specifically, for participants in Cohorts A3 and A4: Treatment naïve participants unfit for induction chemotherapy for AML as defined by the following: Age >= 70 or age 65 to 69 years with at least one of the following: ECOG performance status of 2, Intermediate I/II or adverse risk cytogenetic and molecular alterations per ELN 2010 guidelines or secondary AML, or other comorbidity judged incompatible with intensive chemotherapy
• Adequate end-organ function
• Willing and able to undergo a pre-treatment bone marrow aspirate and biopsy and subsequent bone marrow aspirates and biopsies during treatment
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of less than (<) 1 percent (%) per year during the treatment period and for at least 30 days after the last dose of guadecitabine or 5 months after the last dose of atezolizumab, whichever is longer
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm

Exclusion Criteria:

• In Cohorts A3 and A4 only, participants with AML eligible for standard intensive induction therapy with an anthracycline and cytarabine
• Prior allogeneic stem cell transplant or solid organ transplant
• Active central nervous system involvement by leukemia
• Pregnant or lactating, or intending to become pregnant during the study
• History of idiopathic pulmonary fibrosis, organizing pneumonitis, drug-induced pneumonitis, idiopathic pneumonitis, or autoimmune disease
• Treatment with investigational therapy within 14 days prior to initiation of study drug
• Any approved AML-related therapy within 14 days prior to enrollment
• Immunosuppressive therapy within 6 weeks of Cycle 1, Day 1
• Daily requirement for corticosteroids (> 10 mg prednisone daily or equivalent) (except for inhalation corticosteroids) within 2 weeks prior to Cycle 1, Day 1
• Prior treatment with immune checkpoint blockade therapies (anti-cytotoxic T-lymphocyte-associated protein 4 [anti-CTLA-4], anti-programmed death-1 [anti-PD-1] or anti-PD-L1) or immune agonists (anti-cluster of differentiation [CD]137, anti-CD40, anti-OX40)
• Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to Cycle 1, Day 1
• Treatment with denosumab (or other receptor activator of nuclear factor kappa-B ligand [RANKL] inhibitor) 4 weeks before the first dose and for 10 weeks after the last dose of atezolizumab
• Administration of a live, attenuated vaccine within 4 weeks of Cycle 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study
• Planned major surgery during the study
• Positive for hepatitis C virus (HCV) antibody at screening
• Active hepatitis B virus (HBV) infection
• Positive for human immunodeficiency virus (HIV)
• Illicit drug or alcohol abuse within 12 months prior to screening
• Poor peripheral venous access
• Active infection
• Serious infection requiring hospitalization or intravenous (IV) antibiotics within 14 days prior to enrollment
• Any serious medical condition or abnormality in clinical laboratory tests
• History or presence of an abnormal electrocardiogram (ECG)
• History of other malignancy within 2 years prior to screening
• Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab or guadecitabine formulations
• History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins