Inclusion Criteria:
* Participants with documented diagnosis of intermediate-2 or high-risk primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis or Post-essential Thrombocythemia Myelofibrosis.
* Participant must be ineligible due to age, comorbidities, or unfit for unrelated or unmatched donor transplantation or unwilling to undergo stem cell transplantation at time of study entry.
* Eastern Cooperative Oncology Group (ECOG) of 0, 1, or 2.
* Prior treatment must meet at least one of the following criteria:
* Prior or current treatment with ruxolitinib and no prior treatment with a Bromodomain and Extra-Terminal motif (BET) proteins inhibitor or another Janus Kinase 2 (JAK-2) inhibitor, and meet all of the following criteria:
* Ruxolitinib treatment must meet at least one of the following criteria:
* Ruxolitinib treatment for \>=24 weeks with lack of efficacy defined as a lack of spleen response (refractory) or a loss of spleen or symptom response (relapsed)
* Ruxolitinib treatment for \<24 weeks with documented disease progression on spleen measurements while on ruxolitinib as defined in the protocol:
* Ruxolitinib treatment for \>=28 days with intolerance defined as new red blood cell transfusion requirement (at least 2 units/month for 2 months) while receiving a total daily ruxolitinib dose of \>=30 mg but unable to reduce dose further due to lack of efficacy.
* If receiving ruxolitinib at the time of screening, must currently be on a stable dose \>=10 mg twice daily of ruxolitinib for \>=4 weeks prior to the 1st dose of navitoclax.
* Participant has at least 2 symptoms each with a score \>=3 or a total score of \>=12, as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 on at least 4 out of 7 days during screening prior to study drug dosing; OR
* Prior treatment with a JAK-2 inhibitor and meet one of the following criteria:
* Prior treatment with a JAK-2 inhibitor for at least 12 weeks
* Prior treatment with a JAK-2 inhibitor for \>=28 days complicated by either development of red blood cell transfusion requirement (at least 2 units/month for 2 months) OR Grade \>= 3 adverse events of thrombocytopenia, anemia, hematoma and/or hemorrhage while on JAK-2 inhibitor treatment; OR
* No prior treatment with a JAK-2 or BET inhibitor.
* Participant has splenomegaly as defined in the protocol.
* Participant must meet the laboratory parameters (adequate bone marrow, renal and hepatic function) as defined in the protocol.
Exclusion Criteria:
* Splenic irradiation within 6 months prior to screening, or prior splenectomy.
* Leukemic transformation (\> 10% blasts in peripheral blood or bone marrow aspirate/biopsy).
* Participant is currently on medications that interfere with coagulation (including warfarin) or platelet function within 3 days prior to the first dose of study drug or during the study treatment period with the exception of low dose aspirin (up to 100 mg/day) and low-molecular-weight heparin.
* Prior therapy with a BH3 mimetic compound or stem cell transplantation.
* Participant has received strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin) or moderate CYP3A inhibitors (e.g., fluconazole) within 14 days prior to the administration of the first dose of study drug.
